TW201713613A - New difluoroketamide derivatives - Google Patents

Abstract

The invention provides novel compounds having the general formula (I) wherein R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as described herein, compositions including the compounds and methods of using the compounds.

Description

Neodifluoroketone oxime derivatives

The present invention relates to organic compounds useful in disease therapy or disease prevention methods in mammals, and in particular to HtrA1-mediated eye diseases (such as wet or dry age-related macular degeneration, geographic atrophy). , diabetic retinopathy, retinopathy of prematurity and polypoidal choroidal vasculopathy, or a serine protease HtrA1 inhibitor.

The present invention provides novel compounds of formula (I):

Wherein R ¹ is alkyl, substituted cycloalkyl, haloalkyl, substituted heterocycloalkylalkyl, substituted arylalkyl or substituted heteroarylalkyl, wherein substituted ring An alkyl group, a substituted heterocycloalkylalkyl group, a substituted arylalkyl group, and a substituted heteroarylalkyl group are substituted by R ¹⁰ , R ¹¹ and R ¹² ; R ² , R ³ , R ⁴ , R ⁶ , R ⁷ and R ⁹ are independently selected from H, alkyl and cycloalkyl; R ⁵ is substituted aryl, substituted arylalkyl, substituted heteroaryl or substituted hetero arylalkyl, wherein the substituted aryl group, substituted aryl group of, ^13, R ¹⁴ and R ¹⁵ substituents of substituted aryl and substituted heteroaryl of heteroarylalkyl line through R; R ⁸ lines Substituted adamantylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted bicycloalkylalkyl, substituted aryl, substituted arylalkyl, Substituted arylalkenyl, substituted diarylalkyl, substituted aryloxyalkyl, substituted diaryloxyalkyl, substituted arylaryloxyalkyl, substituted hetero Arylaryloxyalkyl group a heteroaryl group, a substituted heteroarylalkyl group, a substituted heteroarylalkenyl group, a substituted arylheteroarylalkyl group, a substituted arylheteroaryloxyalkyl group, or a substituted Aryloxyheteroarylalkyl, wherein substituted adamantylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted bicycloalkylalkyl, substituted aryl Substituted arylalkyl, substituted arylalkenyl, substituted diarylalkyl, substituted aryloxyalkyl, substituted diaryloxyalkyl, substituted aryl An aryloxyalkyl group, a substituted heteroarylaryloxyalkyl group, a substituted heteroaryl group, a substituted heteroarylalkyl group, a substituted heteroarylalkenyl group, a substituted aryl heteroaryl group An alkyl group, a substituted arylheteroaryloxyalkyl group and a substituted aryloxyheteroarylalkyl group are substituted by R ¹⁶ , R ¹⁷ and R ¹⁸ ; R ¹⁰ , R ¹¹ , R ¹² , R ¹³ R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are independently selected from the group consisting of H, halogen, alkyl, haloalkyl, cycloalkyl, cyano, hydroxy, alkoxy, haloalkoxy and benzene Base; or pharmaceutically acceptable .

The serine protease HtrA1 family is a family of evolutionarily conserved HtrA proteins that inhibit the potential of the serine protease HtrA1 to protect and treat tissue damage caused by degeneration of the retina or photoreceptor cells in the human eye. The pathophysiological correlation of HtrA1 in the progression of age-related macular degeneration has been firmly established by human genetic studies, in which SNPs in the HtrA1 promoter region result in increased HtrA1 transcripts and protein concentrations. In developed countries, age-related macular degeneration is the leading cause of severe and irreversible central visual loss and blindness in individuals over 65 years of age. AMD has Two forms: dry AMD and wet AMD. Wet AMD (also known as exudative AMD) is associated with pathological posterior choroidal neovascularization associated with disruption of the defined Bruch's membrane. Tissue edema caused by leakage of abnormal blood vessels can damage the macula and damage vision, eventually leading to blindness. In dry AMD, it has been reported that there is a drusen in the macula of the eye, and cells in the macula of the eye die due to the progressive accumulation of the drusen, resulting in progressive vision loss. There are three stages in the clinical description of dry AMD: 1) early; 2) intermediate; and 3) late dry AMD. Dry AMD can also progress to wet AMD during any stage of the disease. Therapeutic strategies for wet AMD are present and current standards of care are Lucentis (Genentech/Roche) and Eylea (Regeneron), which are injected intra-glassly with anti-VEGF antibody and anti-VEGFtrap, respectively. There is currently no treatment for preventing visual loss of the dry form and preventing the progression of dry AMD into local atrophy of the retinal tissue. As discussed above, the HtrA1 risk dual gene line is associated with the onset of AMD (highly statistically significant) and reports indicate that the protein is present in the drusen. These and other evidence provide that HtrA1 is a link between the underlying factors involved in the pathophysiology and progression of AMD. This concept is further confirmed in different AMD disease models in which increased HtrA1 protein concentration in retinal tissue has been shown to cause extracellular matrix (ECM) proteins (eg fibronectin, fibulin, and aggregated protein aggregates). The cause of degradation of sugar (aggrecan). The physiological balance between the production and decomposition of the ECM component can establish and maintain an appropriate retinal tissue structure. It has been reported that this balance is lost in the progression of age-related macular degeneration. In particular, it has been reported that fibrin (main fibrin-3, fibrin-5, fibrin-6) is an important group of Bruch's membranes in maintaining the integrity of the elastic layer and the overall organization of the retinal tissue. Minute. Several variants of fibrin-5 and fibrin-3 have been reported to be associated with AMD, and the missense mutation of the fibrin-5 gene is associated with decreased secretion of fibrin-5. Different studies have reported that HtrA1 protease activity is directed to the cleavage of fibrin as a substrate. It is expected that direct inhibition of HtrA1 protease activity can provide a reduction in extracellular basis. The protective effect of degradation of the proteoprotein (specifically, fibrin and fibrionectin), thus preserving the retinal tissue structure. The recognition of human function loss mutations that cause familial ischemic cerebral small vessel disease strongly supports the correlation of HtrA1 in maintaining the physiological homeostasis of ECM components. This molecular mechanism is based on the enhanced signaling level resulting from the hypoxic TGFβ inhibition by HtrA1, which, together with the depletion of HtrA1-mediated degradation of various extracellular matrix components, determines the ischemic small vessels. The reason for the film thickening. Since HtrA1 plays a fundamental role in regulating intracellular signaling pathways (eg, TGFβ) and regulation of ECM protein turnover, HtrA1 is involved in several pathologies such as eye diseases, rheumatoid arthritis, osteoarthritis, and Alzheimer's. Alzheimer's disease and some types of cancer.

The object of the present invention is a method for producing the compound, an intermediate, a pharmaceutical composition, an agent containing the compound of the formula (I), and the like, the salt and the ester thereof, and the like as a therapeutically active substance. Or a pharmaceutically acceptable salt or ester thereof, the use of such a compound for the treatment or prevention of a disease or condition associated with the activity of HtrA1, in particular for wet or dry age-related macular degeneration, Salts or esters for the treatment or prevention of map-like atrophy, diabetic retinopathy, retinopathy of prematurity and polypoidal choroidal vasculopathy.

The term "adamantylalkyl" means an alkyl group wherein one of the hydrogen atoms of the alkyl group has been replaced with an adamantyl group. A specific adamantylalkyl group is an adamantylmethyl group.

The term "alkenyl" means a monovalent straight or branched chain hydrocarbon group having 2 to 7 carbon atoms and at least one double bond. In a particular embodiment, an alkenyl group has 2 to 4 carbon atoms and at least one double bond. Examples of alkenyl groups include ethenyl, propenyl, prop-2-enyl, isopropenyl, n-butenyl and isobutenyl. A particular alkenyl group is a vinyl group.

The term "alkoxy" denotes a radical of the formula -O-R' wherein R' is alkyl. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. A specific example is a methoxy group.

The term "alkyl" denotes a monovalent straight or branched chain saturated hydrocarbon group having from 1 to 12 carbon atoms. In a particular embodiment, the alkyl group has from 1 to 7 carbon atoms, and in a more specific embodiment from 1 to 4 carbon atoms. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a second butyl group, a tert-butyl group, and a pentyl group. The specific alkyl group is isopropyl.

The term "aryl" means a monovalent aromatic carbocyclic monocyclic or bicyclic ring system containing from 6 to 10 carbon ring atoms. Examples of the aryl group include a phenyl group and a naphthyl group. The specific aryl group is a phenyl group.

The term "arylalkenyl" denotes an alkenyl group wherein one of the hydrogen atoms of the alkyl group has been substituted with an aryl group. A specific arylalkenyl phenyl alkenyl group. A specific example of an arylalkenyl group is a phenylvinyl group.

The term "arylalkyl" denotes an alkyl group wherein one of the hydrogen atoms of the alkyl group has been replaced by an aryl group. A specific arylalkyl group is a phenylalkyl group. A specific example of an arylalkyl group is a phenylmethyl group.

The term "arylaryloxyalkyl" denotes an alkyl group wherein one hydrogen atom of the alkyl group has been replaced by an aryl group and the other hydrogen atom of the alkyl group has been replaced with an aryloxy group. A specific aryl aryloxyalkyl group is a phenylphenoxyalkyl group. A specific example of an arylaryloxyalkyl group is phenylphenoxyethyl.

The term "arylheteroarylalkyl" denotes an alkyl group wherein one hydrogen atom of the alkyl group has been replaced by an aryl group and the other hydrogen atom of the alkyl group has been replaced with a heteroaryl group.

The term "aryloxy" means a group of the formula -O-R' wherein R' is an aryl group. A specific example of the aryloxy group is a group wherein R' is a phenyl group.

The term "aryloxyalkyl" denotes an alkyl group wherein one of the hydrogen atoms of the alkyl group has been replaced by an aryloxy group. A specific example of an aryloxyalkyl group is a phenoxyalkyl group. Another specific example is phenoxymethyl.

The term "heteroarylaryloxyalkyl" denotes an alkyl group wherein one hydrogen atom of the alkyl group has been replaced by a heteroaryl group and the other hydrogen atom of the alkyl group has been replaced with an aryloxy group. A specific heteroarylaryloxyalkyl group is a pyridylphenoxyalkyl group. Specificity of heteroaryl aryloxyalkyl An example is pyridylphenoxyethyl.

The term "aryloxyheteroarylalkyl" means an alkyl group wherein one hydrogen atom of the alkyl group has been replaced by an aryloxy group and the other hydrogen atom of the alkyl group has been substituted with a heteroaryl group. The term "bicyclic ring system" means two via a single bond or double bond (an extended ring bicyclic ring system), via a series of three or more shared atoms (bridged bicyclic ring systems) or via a shared single atom ( A ring that is fused to each other and fused to each other. The bicyclic ring system can be saturated, partially unsaturated, unsaturated or aromatic. The bicyclic ring system may comprise a hetero atom selected from the group consisting of N, O and S.

The term "cyano" denotes a -C≡N group.

The term "cycloalkyl" denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group having from 3 to 10 ring carbon atoms. In a particular embodiment, a cycloalkyl group represents a monovalent saturated monocyclic hydrocarbon group having from 3 to 8 ring carbon atoms. Bicyclic means a ring system consisting of two saturated carbon rings with two common carbon atoms. Examples of monocyclic cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples of bicyclic cycloalkyl groups are bicyclo [2.2.1] heptyl or bicyclo [2.2.2] octyl. Particular monocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. More specifically, a monocyclic cycloalkyl-based cyclohexyl group.

The term "cycloalkylalkyl" denotes an alkyl group wherein at least one hydrogen atom of the alkyl group has been replaced by a cycloalkyl group. Examples of cycloalkylalkyl groups include cyclopropylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylpropyl, 2-cyclopropylbutyl, cyclopentylbutyl, cyclohexylmethyl Cyclohexylethyl, bicyclo[4.1.0]heptylmethyl, bicyclo[4.1.0]heptylethyl, bicyclo[2.2.2]octylmethyl and bicyclo[2.2.2]octyl Base ethyl. Specific examples of cycloalkylalkyl are cyclohexylmethyl, cyclohexylethyl, bicyclo[4.1.0]heptylmethyl, bicyclo[4.1.0]heptylethyl, bicyclo[2.2.2] Octylmethyl and bicyclo[2.2.2]octylethyl. Another specific example is a cycloalkylalkyl cyclohexylethyl group.

The term "diarylalkyl" denotes an alkyl group wherein the two hydrogen atoms of the alkyl group have been replaced by two independently selected aryl groups. A specific diarylalkyl group is a diphenylalkyl group. Examples of diarylalkyl groups are diphenylmethyl and diphenylethyl. Specific examples of diarylalkyl groups are benzene Base ethyl. Another specific example is 2,2-diphenylethyl.

The term "diaryloxyalkyl" denotes an alkyl group wherein the two hydrogen atoms of the alkyl group have been replaced by two independently selected aryloxy groups. A specific diaryloxyalkyl group is a diphenoxyalkyl group. A specific example of a diaryloxyethyl group is 1,2-diphenoxyethyl.

The term "bicycloalkylalkyl" denotes an alkyl group wherein the two hydrogen atoms of the alkyl group have been replaced by two independently selected cycloalkyl groups.

The term "haloalkoxy" denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by the same or different halogen atom. The term "perfluoroalkoxy" denotes an alkoxy group wherein all of the hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms. Examples of haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy, and pentafluoroethane. Oxygen. A specific haloalkoxy-based trifluoromethoxy group.

The term "haloalkyl" denotes an alkyl group wherein at least one hydrogen atom of the alkyl group has been replaced by the same or different halogen atoms. The term "perfluoroalkyl" denotes an alkyl group wherein all of the hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyl and pentafluoroethyl. A specific haloalkyl group is a trifluoromethyl group.

The terms "halogen" and "halo" are used interchangeably herein and mean fluoro, chloro, bromo or iodo. A specific halogen is chlorine.

The term "heteroaryl" denotes a monovalent aromatic heterocyclic monocyclic or bicyclic ring system having from 5 to 12 ring atoms, which comprises 1, 2, 3 or 4 heteroatoms selected from N, O and S, The remaining ring atomic carbon. Examples of heteroaryl groups include pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, Pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, aziridine, diazenium, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, fluorenyl, isoindole Base, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazole , benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, indolyl, quinolyl, isoquinolinyl, quinazolinyl, quinoxalinyl and Benzothiophenyl group.

The term "arylheteroaryloxyalkyl" denotes an alkyl group wherein one hydrogen atom of the alkyl group has been replaced by an aryl group and the other hydrogen atom of the alkyl group has been replaced with a heteroaryloxy group. A specific arylheteroaryloxyalkylphenylpyridyloxyalkyl group. A specific example of an arylheteroaryloxyalkyl group is phenylpyridyloxyethyl.

The term "heteroarylalkenyl" denotes an alkenyl group wherein one of the hydrogen atoms of the alkenyl group has been substituted with a heteroaryl group.

The term "heteroarylalkyl" denotes an alkyl group wherein one of the hydrogen atoms of the alkyl group has been replaced by a heteroaryl group.

The term "heterocycloalkyl" denotes a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system having from 4 to 9 ring atoms, which contains 1, 2 or 3 ring heteroatoms selected from N, O and S, The remaining ring atomic carbon. Bicyclic means consisting of two rings having two atoms sharing a ring, ie, a bridge single bond separating the two rings or a chain having one or two ring atoms. Examples of monocyclic saturated heterocycloalkyl groups are 4,5-dihydro-oxazolyl, oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, Tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazine Base, morpholinyl, thiomorpholinyl, 1,1-di-oxy-thiomorpholin-4-yl, azepanyl, diazepine, homopiperazinyl or oxazepine Heptyl. Examples of bicyclic saturated heterocycloalkyl groups are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]fluorenyl, 3-oxa-9-aza-bicyclo[3.3.1]fluorenyl or 3-thia-9-aza-bicyclo[3.3. 1] 壬基. Examples of partially unsaturated heterocycloalkyl groups are dihydrofuranyl, imidazolidinyl, dihydrooxazolyl, tetrahydropyridyl or dihydropyranyl. A specific example of a heterocycloalkyl group is morpholinyl.

The term "heterocycloalkylalkyl" denotes an alkyl group wherein one of the hydrogen atoms of the alkyl group has been replaced by a heterocycloalkyl group. A specific example of a heterocycloalkyl group is morpholinylethyl.

The term "phenoxy" means a group of the formula -O-R' wherein R' is phenyl.

The term "phenoxyalkyl" denotes an alkyl group wherein one hydrogen atom of the alkyl group has been replaced by a phenoxy group. A specific example of a phenoxyalkyl group is a phenoxymethyl group.

The term "phenylphenoxyalkyl" denotes an alkyl group wherein one hydrogen atom of the alkyl group has been replaced by a phenoxy group and the other hydrogen atom of the alkyl group has been replaced with a phenyl group.

The term "pharmaceutically acceptable salts" refers to salts which are biologically and otherwise desirable for retaining the biological effectiveness and properties of the free base or free acid. Such salts are with inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, specifically hydrochloric acid) and organic acids (such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid). , malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylhydrazine Cysteine and the like) are formed. Alternatively, such salts can be prepared by the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, and the like. Salts derived from organic bases include, but are not limited to, primary, secondary and tertiary amines, substituted amines (which include naturally occurring substituted amines), cyclic amines, and basic ion exchange resins such as isopropylamine. a salt of trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resin and the like. Particular pharmaceutically acceptable salts of the compounds of formula (I) are the hydrochloride, methanesulfonate and citrate salts.

"Pharmaceutically acceptable ester" means that the compound of formula (I) can be derivatized at a functional group to provide a derivative which can be converted in vivo to the parent compound. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives such as methoxymethyl ester, methylthiomethyl ester and neopentyloxymethyl ester. Furthermore, any physiologically acceptable equivalent of a compound of formula (I) (similar to a metabolically labile ester, such as a parent compound of formula (I) in vivo) is also within the scope of the invention Inside.

The term "protecting group" (PG) means selectively blocking reactivity in a polyfunctional compound. The site is such that the chemical reaction can be selectively carried out at another unprotected reactive site with a conventionally relevant meaning in synthetic chemistry. The protecting group can be removed at a suitable site. Exemplary protecting groups are amine protecting groups, carbonyl protecting groups or hydroxy protecting groups. Particular protecting groups are the butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn) groups. Other specific protecting groups are the butoxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc) groups. More specific protecting groups are the third butoxycarbonyl (Boc) groups.

The abbreviation uM means micro-mole and is equivalent to the symbol μM.

The abbreviation uL means microliter and is equivalent to the symbol μL.

The abbreviation ug means microgram and is equivalent to the symbol μg.

The compound of formula (I) may contain several asymmetric centers and may exist in the form of optically pure isomers, mixtures of mirror image isomers (such as, for example, racemates), optically pure non-image isomers, A mixture of mirror image isomers, a non-planoisomeric racemate or a mixture of non-planoisomeric racemates.

According to the Cahn-Ingold-Prelog convention, asymmetric carbon atoms can have an "R" or "S" configuration.

Depending on the individual compounds, and the exposure conditions, the compound I CF ₂ - one part system part, or all of the present form of their hydrates. Thus, ₂ CF - described in any one part of both always described ketone and hydrate form.

A further embodiment of the invention is a compound according to formula (I), and a pharmaceutically acceptable salt or ester thereof, as described herein, in particular, a compound according to formula (I) as described herein, and a pharmaceutically acceptable Accepted salts, more specifically, are compounds according to formula (I) as described herein.

A further embodiment of the invention is a compound according to formula (I) as described herein, wherein R ¹ is alkyl, substituted cycloalkyl, haloalkyl, substituted heterocycloalkylalkyl, substituted An arylalkyl group or a substituted heteroarylalkyl group, wherein a substituted cycloalkyl group, a substituted heterocycloalkylalkyl group, a substituted arylalkyl group, and a substituted heteroarylalkyl group Substituted by R ¹⁰ , R ¹¹ and R ¹² ; R ² , R ³ , R ⁴ , R ⁶ , R ⁷ and R ⁹ are independently selected from H, alkyl and cycloalkyl; R ⁵ is substituted aryl , substituted arylalkyl, substituted heteroaryl or substituted heteroarylalkyl, wherein substituted aryl, substituted arylalkyl, substituted heteroaryl, and substituted a heteroarylalkyl group substituted with R ¹³ , R ¹⁴ and R ¹⁵ ; R ⁸ a substituted adamantylalkyl group, a substituted cycloalkyl group, a substituted cycloalkylalkyl group, a substituted bicyclic ring Alkylalkyl, substituted aryl, substituted arylalkyl, substituted arylalkenyl, substituted diarylalkyl, substituted aryloxyalkyl, substituted diaryl Oxyalkyl group Alternate aryl aryloxyalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heteroarylalkenyl, substituted arylheteroarylalkyl or substituted aryl Oxyheteroarylalkyl, wherein substituted adamantylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted bicycloalkylalkyl, substituted aryl, Substituted arylalkyl, substituted arylalkenyl, substituted diarylalkyl, substituted aryloxyalkyl, substituted diaryloxyalkyl, substituted arylaryl An oxyalkyl group, a substituted heteroaryl group, a substituted heteroarylalkyl group, a substituted heteroarylalkenyl group, a substituted arylheteroarylalkyl group, and a substituted aryloxyheteroaryl group The alkyl group is substituted by R ¹⁶ , R ¹⁷ and R ¹⁸ ; R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are independently selected from H, halogen, alkane. a group, a haloalkyl group, a cycloalkyl group, a cyano group, a hydroxyl group, an alkoxy group, a haloalkoxy group, and a phenyl group; or a pharmaceutically acceptable salt.

Another embodiment of the present invention based embodiment described herein as the compounds of formula (I) according to the, in which R ¹ lines alkyl, haloalkyl, substituted heterocycloalkyl of the substituted alkyl or phenylalkyl, wherein The substituted heterocycloalkylalkyl group and the substituted phenylalkyl group are substituted by R ¹⁰ , R ¹¹ and R ¹² .

A particular embodiment of the invention is a compound according to formula (I) as described herein, wherein R ¹ is haloalkyl, a further embodiment of the invention is a compound according to formula (I) as described herein, wherein R ¹⁰ , R ¹¹ and R ¹² are H.

Another embodiment of the present invention-based embodiments of the compound as described herein according to formula (I), wherein R ^{9 is} H. Department

A particular embodiment of the invention is a compound according to formula (I) as described herein, wherein R ² is alkyl.

Another particular embodiment of the present invention-based embodiments of the compound as described herein according to formula (I), wherein R ³ line H.

A further embodiment of the invention is a compound according to formula (I) as described herein, wherein R ⁴ is H.

The present invention is also based phenylalkyl based on the compound described herein as formula (I) of the, wherein R ⁵ based substituted or substituted phenyl group of the phenylalkyl, wherein substituted phenyl and substituted of the Substituted by R ¹³ , R ¹⁴ and R ¹⁵ .

One embodiment of the present invention is based embodiment described herein as the compounds of formula (I) of the, wherein R ^13, R ¹⁴ and R ¹⁵ are independently selected from H, halogen and alkoxy.

One embodiment of the present invention, a particular embodiment of the system described herein as a compound of formula (I) of the, wherein R ^13, R ¹⁴ and R ¹⁵ are independently selected from H and halo.

A further embodiment of the invention is a compound according to formula (I) as described herein, wherein R ⁸ is substituted phenylalkyl, substituted phenylalkenyl, substituted diphenylalkyl, via a substituted phenoxyalkyl group, a substituted pyridylphenoxyalkyl group, a substituted phenylpyridyloxyalkyl group or a substituted phenylphenoxyalkyl group, wherein the substituted phenylalkyl group, The substituted phenylalkenyl group, the substituted diphenylalkyl group, the substituted phenoxyalkyl group, and the substituted phenylphenoxyalkyl group are substituted with R ¹⁶ , R ¹⁷ and R ¹⁸ .

A further embodiment of the invention is a compound according to formula (I) as described herein, wherein R ⁸ is substituted phenylalkyl, substituted phenylalkenyl, substituted diphenylalkyl, via a substituted phenoxyalkyl group or a substituted phenylphenoxyalkyl group, wherein a substituted phenylalkyl group, a substituted phenyl alkenyl group, a substituted diphenylalkyl group, a substituted phenoxy group The alkyl group and the substituted phenylphenoxyalkyl group are substituted by R ¹⁶ , R ¹⁷ and R ¹⁸ .

A particular embodiment of the invention is a compound according to formula (I) as described herein, wherein R ⁸ is substituted phenoxyalkyl or substituted phenylphenoxyalkyl, wherein substituted phenoxy The alkyl group and the substituted phenylphenoxyalkyl group are substituted by R ¹⁶ , R ¹⁷ and R ¹⁸ .

Another embodiment of the present invention-based embodiments of the compound as described herein according to formula (I), wherein R ^16, R ¹⁷ and R ¹⁸ are independently selected from H and halo.

A more specific embodiment of the invention is a compound according to formula (I) as described herein, wherein the compound has formula (Ia).

A further embodiment of the invention is a compound according to formula (I) as described herein, wherein R ¹ is haloalkyl; R ² is alkyl; R ³ , R ⁴ , R ⁶ , R ⁷ and R ⁹ are H R ⁵ is a substituted phenyl or substituted phenylalkyl group, wherein the substituted phenyl group and the substituted phenylalkyl group are substituted by R ¹³ , R ¹⁴ and R ¹⁵ ; R ⁸ is substituted a phenoxyalkyl group or a substituted phenylphenoxyalkyl group, wherein the substituted phenoxyalkyl group and the substituted phenylphenoxyalkyl group are substituted by R ¹⁶ , R ¹⁷ and R ¹⁸ ; ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are independently selected from H and halogen; or a pharmaceutically acceptable salt.

A specific example of a compound of formula (I) as described herein is selected from the group consisting of: (4S)-4-[[(2S)-2-[3-(3-chlorophenyl)propanylamino]-3-benzene Acryl]amino]-2,2-difluoro-5-methyl-N-(2-morpholin-4-ylethyl)-3-oxohexylamine; (S)-4 -((S)-2-((E)-3-(3,5-dichlorophenyl)acrylamido)-2-phenylethylamino)-2,2-difluoro-5- Methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-(3-(3-chlorophenyl) Propioninyl-3-phenylpropanylamino)-2,2-difluoro-5-methyl-3-oxo-N-phenethylhexylamine; (S)-4-( (S)-2-(3-(3-Chlorophenyl)propanylamino)-3-phenylpropanylamino)-2,2-difluoro-5-methyl-3-oxo- N-(3,3,3-trifluoropropyl)hexylamine; (S)-4-((S)-2-(3-(3,4-dichlorophenyl)propanylamino)- 3-phenylpropionamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S)- 4-((S)-2-(2-(3-chlorophenoxy)ethylamino)-3-phenylpropanamido)-2,2-difluoro-5-methyl-3- oxy-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-(2-(3,4-dichlorophenoxy)B Amidino)-3-phenylpropanylamino)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanide Amine; (S)-4-((S)-2-(3-(3,5-dichlorophenyl)propanylamino)-3-phenylpropanylamino)-2,2-difluoro -5-methyl-3-oxirane-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-(2-(3,5) -dichlorophenoxy)ethylamino)-3-phenylpropanylamino)-2,2-difluoro-5-methyl-3-o-oxy-N-(2,2,2- Trifluoroethyl)hexylamine; (S)-4-((S)-2-(3-(3-chlorophenyl)propanamido)-3-phenylpropanamido)-2, 2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-(2- (3,4-Dichlorophenoxy)ethylamino)-3-phenylpropanylamino)-2,2-difluoro-5-methyl-N-(2-morpholinylethyl)- 3-oxo hexylamine; (S)-4-((S)-2-(2-(3-chlorophenoxy)ethylamino)-3-phenylpropanamido)-2,2-difluoro-5-A -N-(2-morpholinethyl)-3-oxohexylamine; (S)-4-((S)-2-(2-(3,5-dichlorophenoxy)B醯Amino)-3-phenylpropanylamino)-2,2-difluoro-5-methyl-N-(2-morpholinylethyl)-3-oxohexylamine; (S) -4-((S)-2-(3-(3,5-dichlorophenyl)propanylamino)-3-phenylpropanamido)-2,2-difluoro-5-methyl -N-(2-morpholinethyl)-3-oxohexylamine; (S)-4-((S)-2-(3-(3,4-dichlorophenyl)propanamide (3-phenylpropionamido)-2,2-difluoro-5-methyl-N-(2-morpholinethyl)-3-oxohexylamine; (S)-4 -((S)-2-(3-(3,4-dichlorophenyl)propanylamino)-3-phenylpropanamido)-2,2-difluoro-5-methyl-3 -Sideoxy-N-phenethylhexylamine; (S)-4-((S)-2-(2-(3-chlorophenoxy)acetamido)-3-phenylpropionate Amino)-2,2-difluoro-5-methyl-3-o-oxy-N-phenethylhexylamine; (S)-4-((S)-2-(3-(3, 4-Dichlorophenyl)propanylamino)-3-phenylpropanylamino)-2,2-difluoro-5-methyl-3-oxo-N-(3,3,3- Trifluoropropyl)hexylamine; (S)-4-((S)-2-(2-(3,5-dichlorophenoxy)acetamido)-3-phenylpropanamido )-2,2-difluoro-5- 3-O-oxy-N-(3,3,3-trifluoropropyl)hexylamine; (S)-4-((S)-2-(2-(3-chlorophenoxy)) Acetylamino)-3-phenylpropanylamino)-2,2-difluoro-5-methyl-3-oxo-N-(3,3,3-trifluoropropyl)hexanide Amine; (S)-4-((S)-2-(3-(3,5-dichlorophenyl)propanylamino)-3-phenylpropanylamino)-2,2-difluoro -5-methyl-3-oxirane-N-(3,3,3-trifluoropropyl)hexylamine; (S)-4-((S)-2-(2-(3,4) -dichlorophenoxy)ethylamino)-3-phenylpropanylamino)-2,2-difluoro-5-methyl-3-oxirane-N-(3,3,3- Trifluoropropyl)hexylamine; (S)-4-((S)-3-(4-chlorophenyl)-2-(3-(3,4-dichlorophenyl)propanylamino) Propioninyl)-2,2-difluoro-5-methyl-3-oxo-N-phenethylhexylamine; (S)-4-((S)-2-(3-( 3,4-Dichlorophenyl)propanylamino)-3-(3,4-dimethoxyphenyl)propanylamino)-2,2-difluoro-5-methyl-3- side Oxy-N-phenethyl hexylamine; (S)-4-((S)-2-(3-(3,4-dichlorophenyl)propanylamino)-3-(3,4-dimethoxyphenyl)propanylamino -2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-3 -(3,4-dichlorophenyl)-2-(3-(3,4-dichlorophenyl)propanylamino)propanylamino)-2,2-difluoro-5-methyl- 3-sided oxy-N-phenethyl hexylamine; (S)-4-((S)-3-(4-chlorophenyl)-2-(2-(3,5-dichlorophenoxy) Ethylamino)propanylamino)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; S)-4-((S)-2-(2-(3,5-Dichlorophenoxy)acetamido)-3-(3,4-dichlorophenyl)propanylamino)- 2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-( 2-(3,5-Dichlorophenoxy)ethylamino)-3-phenylpropanylamino)-N-ethyl-2,2-difluoro-5-methyl-3-sideoxy (S)-4-((S)-2-(2-(3,5-dichlorophenoxy)ethylamino)-3-phenylpropanamido)-2, 2-difluoro-N-isobutyl-5-methyl-3-oxohexylamine; (S)-4-((S)-2-(2-(3,5-dichlorophenoxy) Ethylamino)-3-(3,4-dichlorophenyl)propanylamino)-N-ethyl-2,2-difluoro-5-methyl-3-oxiranyl oxime Amine; (S)-4-((S)-2-(2-(3,5- Chlorophenoxy)ethylamino)-3-(3,4-dichlorophenyl)propanylamino)-2,2-difluoro-N-isobutyl-5-methyl-3- side Oxyhexylamine; (S)-4-((S)-2-(2-(3,5-dichlorophenoxy)acetamido)-3-(3,4-difluorophenyl) (Propyl)amino-2,2-difluoro-N-isobutyl-5-methyl-3-oxohexylamine; (S)-4-((S)-3-(4- Chlorophenyl)-2-(2-(3,5-dichlorophenoxy)ethylammonium)propanylamino)-2,2-difluoro-5-methyl-3-oxo- N-(3,3,3-trifluoropropyl)hexylamine; (S)-4-((S)-2-(2-(3,5-dichlorophenoxy)ethylamino) -3-(3,4-dichlorophenyl)propanylamino)-2,2-difluoro-5-methyl-3-oxo-N-(3,3,3-trifluoropropyl Hexylamine; (S)-4-((S)-2-(2-(3,5-dichlorophenoxy)acetamido)-3-(3,4-difluorophenyl) Propioninyl)-2,2-difluoro-5-methyl-3-oxo-N-(3,3,3-trifluoropropyl)hexylamine; (S)-4-(( S)-2-(2-(3,5-Dichlorophenoxy)acetamido)-3-(3,4-dimethoxyphenyl)propanylamino)-2,2-di Fluoro-5-methyl-3-o-oxy-N-(3,3,3-trifluoropropyl)hexylamine; (S)-4-((S)-2-(2-(3,5-Dichlorophenoxy)acetamido)-3-phenylpropanamido)-2,2-difluoro- 5-methyl-3-oxo-N-propylhexylamine; (S)-4-((S)-2-(2-(3,5-dichlorophenoxy)ethinylamino )-3-phenylpropanylamino)-2,2-difluoro-5-methyl-N-neopentyl-3-oxohexylamine; (4S)-4-((2S)- 2-(3-(3,4-Dichlorophenyl)-3-phenylpropanylamino)-3-phenylpropanamido)-2,2-difluoro-5-methyl-3- oxy-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-3-(4-chlorophenyl)-2-(2-(3) ,5-dichlorophenoxy)ethylammonium)propanylamino)-2,2-difluoro-5-methyl-3-oxo-N-propylhexylamine; (S)- 4-((S)-2-(2-(3,5-Dichlorophenoxy)acetamido)-3-(3,4-difluorophenyl)propanylamino)-2,2 -difluoro-5-methyl-N-neopentyl-3-oxohexylamine; (S)-4-((S)-2-(2-(3,5-dichlorophenoxy) Ethylamino)-3-(3,4-difluorophenyl)propanylamino)-2,2-difluoro-5-methyl-3-oxo-N-(2,2, 2-(trifluoroethyl)hexylamine; (S)-4-((S)-2-(2-(3,5-dichlorophenoxy)acetamido)-3-(3,4 -dimethoxyphenyl)propanylamino)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-((2S)-2-(3-(3 ,4-dichlorophenyl)-3-(4-methoxyphenyl)propanylamino)-3-phenylpropanamido)-2,2-difluoro-5-methyl-3- oxy-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-((E)-3-(3,4-dichlorobenzene) (A) acrylamido)-3-phenylpropanylamino)-2,2-difluoro-5-methyl-3-oxo-N-propylhexylamine; (S)-4- ((S)-2-((E)-3-(3,4-Dichlorophenyl)acrylamido)-3-phenylpropanamido)-2,2-difluoro-5-A -N-neopentyl-3-oxohexylamine; (S)-4-((S)-2-((E)-3-(3,4-dichlorophenyl)propenylamine 3-phenylpropionamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; S)-4-((S)-2-((E)-3-(3,5-dichlorophenyl)acrylamido)-3-phenylpropanamido)-2,2-di Fluor-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-(4-chlorophenyl) )-2-(2-(3,5-dichlorophenoxy)acetamido)acetamide (2) 2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)- 2-(3,3-Diphenylpropionamido)-3-phenylpropanylamino)-2,2-difluoro-5-methyl-3-oxo-N-(2,2 ,2-trifluoroethyl)hexylamine; (4S)-4-((2S)-2-(3-(3,5-dichlorophenyl)-3-(4-methoxyphenyl) Propioninyl-3-phenylpropanylamino)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanide Amine; (4S)-4-((2S)-3-(4-chlorophenyl)-2-(3-(3,4-dichlorophenyl)-3-phenylpropanylamino)propanoid Amino)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-((2S) -2-(3-(3,4-Dichlorophenyl)-3-phenylpropanylamino)-3-(4-methoxyphenyl)propanylamino)-2,2-difluoro -5-methyl-3-oxirane-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[[(2S)-2-[[2-(3 ,5-dichlorophenoxy)ethinyl]amino]-2-phenylethenyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-( 2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-(2-(3,5-dichlorophenoxy)ethinyl)-2- (4-fluorophenyl)acetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; 4S)-4-((2S)-2-(3-(3,4-dichloro) Phenyl)-3-phenylpropanylamino)-2-phenylacetamido)-2,2-difluoro-5-methyl-3-o-oxy-N-(2,2,2 -trifluoroethyl)hexylamine; (4S)-4-((2S)-2-(4-chlorophenyl)-2-(3-(3,4-dichlorophenyl)-3-benzene Propionylamino)acetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S )-4-((S)-2-(3-(3,4-dichlorophenyl)propanylamino)-2-phenylethylamino)-2,2-difluoro-5-A 3-O-oxy-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-((2S)-2-(3-(4-bromophenyl)- 3-phenylpropanylamino)-3-phenylpropanylamino)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl Hexylamine; (4S)-4-((2S)-2-(3-(4-bromophenyl)-3-phenylpropanamido)-3-(4-chlorophenyl)propene Amidino)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S )-2-((E)-3-(3,4-dichlorophenyl)acrylamido)-2-phenylacetamido)-2,2-difluoro-5-methyl-3 - alkoxy-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-((E)-3-(3-chlorophenyl)acrylamido)-2-phenylacetamido)-2,2-difluoro- 5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-((E)-3-( 4-chlorophenyl)acrylamido)-2-phenylacetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-tri Fluoroethyl)hexylamine; (4S)-4-((2S)-2-(3-(3,5-dichlorophenyl)-3-phenylpropanamido)-2-phenylethyl Amidino)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S )-2-(4-chlorophenyl)-2-((E)-3-(3,4-dichlorophenyl)propenylamino)acetamido)-2,2-difluoro-5 -methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-(4-chlorophenyl)-2 -((E)-3-(3,5-dichlorophenyl)acrylamidoamino)acetamido)-2,2-difluoro-5-methyl-3-oxo-N-( 2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-(4-chlorophenyl)-2-((E)-3-(3-chlorobenzene) Acrylamino)acetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; S)-4-((S)-2-(4-chlorophenyl)-2-((E)-3-(4-chlorophenyl)propenylamino)acetamido)-2,2 -difluoro-5-methyl-3-o-oxy-N-(2,2,2-trifluoroethyl Hexylamine; (4S)-4-((2S)-2-(3-(3,4-dichlorophenyl)-3-phenoxypropylamino)-2-phenylacetamide -2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-((2S)- 2-(3-(3,4-Dichlorophenyl)-3-phenoxypropylamino)-3-phenylpropanamido)-2,2-difluoro-5-methyl-3 -Sideoxy-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-((2S)-2-(3-(4-chlorophenoxy)-3- (3,4-dichlorophenyl)propanylamino)-2-phenylacetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2 ,2-trifluoroethyl)hexylamine; (4S)-4-((2S)-2-(3-(4-chlorophenoxy)-3-(3,4-dichlorophenyl)propane Amidino)-3-phenylpropanylamino)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine (S)-4-((S)-2-((S)-3-(3,5-dichlorophenyl)-3-phenylpropanamido)-2-phenylacetamido -2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-((2S)-2 -(3-(3,5-difluorophenyl)-3-(4-methoxyphenyl)propanamido)-2-phenylacetamido)-2,2-difluoro-5 -methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanide Amine; (4S)-4-((2S)-2-(3-(3,5-difluorophenyl)-3-(4-methoxyphenyl)propanylamino)-3-phenyl Propioninyl)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-(( S)-2-(4-chlorophenyl)-2-((S)-3-(3,5-dichlorophenyl)-3-phenylpropanylamino)acetamido)-2, 2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-((R) )-3-(3,5-dichlorophenyl)-3-phenylpropanylamino)-2-phenylacetamido)-2,2-difluoro-5-methyl-3- side oxy-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-(4-chlorophenyl)-2-((R)-3 -(3,5-dichlorophenyl)-3-phenylpropanylamino)acetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2, 2,2-Trifluoroethyl)hexylamine; and pharmaceutically acceptable salts thereof.

A further specific example of a compound of formula (I) as described herein is selected from the group consisting of: (4S)-4-[[(2S)-2-[[(3S)-3-(3-chlorophenoxy)-3-) Phenylpropanyl]amino]-2-(4-chlorophenyl)ethenyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2, 2,2-trifluoroethyl)hexylamine; (4S)-4-[[(2S)-2-[[(3S)-3-(3-chlorophenoxy)-3-phenylpropanthene) Amino]-2-phenylethenyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl) Hexylamine; (4S)-4-[[(2S)-2-[3-(3,4-dichlorophenyl)propanylamino]-3-(4-methoxyphenyl)propene Mercapto]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[ [(2S)-2-[[2-(3,5-Dichlorophenoxy)ethinyl]amino]-2-(4-methoxyphenyl)ethinyl]amino]-2 ,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[[(2S)-2-[ [3-(3-Chlorophenyl)-3-phenylpropanyl]amino]-2-phenylethenyl]amino]-2,2-difluoro-5-methyl-3- side oxy-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[[(2S)-2-(4-chlorophenyl)-2-[[3-( 3-chlorophenyl)-3-phenylpropanyl]amino] Ethyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4- [[(2S)-2-[[(E)-3-(4-Chlorophenyl)prop-2-enyl]amino]-2-(4-methoxyphenyl)ethenyl] Amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[[(2S) -2-[[3-(3,4-dichlorophenyl)-3-phenylpropanyl]amino]-2-(4-methoxyphenyl)ethenyl]amino]- 2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[[(2S)-2- [[3-(3-Chlorophenoxy)-3-(3,4-dichlorophenyl)propanyl]amino]-2-phenylethenyl]amino]-2,2-di Fluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[[(2S)-2-[[3-( 3-Chlorophenoxy)-3-(3,4-dichlorophenyl)propanyl]amino]-2-(4-chlorophenyl)ethinyl]amino]-2,2-di Fluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[[(2S)-2-[[(3R) 3-(3-chlorophenoxy)-3-phenylpropanyl]amino]-2-phenylethenyl]amino]-2,2-difluoro-5-methyl-3- oxy-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[[(2S)-2-[[(3R)-3-(3-chlorophenoxy) 3-phenylpropenyl]amino]-2-(4-chlorobenzene Ethyl)amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)- 4-[[(2S)-2-[[(3S)-3-(4-chlorophenoxy)-3-(3,4-dichlorophenyl)propanyl]amino]-2-( 4-chlorophenyl)ethinyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[[(2S)-2-[[3-(4-chlorophenoxy)-3-(3,4-dichlorophenyl)propanyl]amino]-2-benzene Ethyl]amino]-2,2-difluoro-5-methyl-N-(2-morpholin-4-ylethyl)-3-oxohexylamine; (4S)-4 -[[(2S)-2-[[(E)-3-(3,4-dichlorophenyl)prop-2-enyl]amino]-2-phenyl Ethyl]amino]-2,2-difluoro-5-methyl-N-(2-morpholin-4-ylethyl)-3-oxohexylamine; (4S)-4- [[(2S)-2-[[2-(3,5-Dichlorophenyl)) thioethyl)]amino]-3-phenylpropanyl]amino]-2,2-di Fluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[[(2S)-2-[[3-( 3-chlorophenoxy)-3-(5-chloropyridin-3-yl)propanyl]amino]-2-phenylethenyl]amino]-2,2-difluoro-5- 3-O-oxy-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[[(2S)-2-[[3-(3-chlorophenyl) )-3-pyridin-3-yl-oxo-propionyl]amino]-2-phenylethenyl]amino]-2,2-difluoro-5-methyl-3-oxirane- N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[[(2S)-2-[[3-(3-chlorophenyl)-3-(5-chloro) Pyridin-3-yl)oxypropanyl]amino]-2-(4-methoxyphenyl)ethenyl]amino]-2,2-difluoro-5-methyl-3- side Oxy-N-(2,2,2-trifluoroethyl)hexylamine; and pharmaceutically acceptable salts thereof.

Other specific examples of compounds of formula (I) as described herein are selected from: (4S)-4-[[(2S)-2-[[2-(3,5-dichlorophenoxy)ethyl)] Amino]-3-phenylpropanyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexan Amine; (4S)-4-[[(2S)-3-(4-chlorophenyl)-2-[[2-(3,5-dichlorophenoxy)ethyl)amino]propanone Amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[[ (2S)-2-(4-chlorophenyl)-2-[[2-(3,5-dichlorophenoxy)ethenyl]amino]ethinyl]amino]-2,2- Difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[[(2S)-2-[[2- (3,5-dichlorophenoxy)ethinyl]amino]-2-phenylethenyl]amino]-2,2-difluoro-5-methyl-3-oxo-N -(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[[(2S)-2-[[3-(3,4-dichlorophenyl)-3-phenoxy) Amidyl]amino]-3-phenylpropanyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoro Ethyl)hexylamine; (4S)-4-[[(2S)-2-[[3-(4-chlorophenoxy)-3-(3,4-dichlorophenyl)propanyl] Amino]- 3-phenylpropionyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S )-4-[[(2S)-2-[[3-(4-chlorophenoxy)-3-(3,4-dichlorophenyl)propanyl]amino]-2-phenylethyl Mercapto]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; and pharmaceutically acceptable salt.

The object of the invention is a process for the manufacture of a compound of formula (I) as described herein.

The preparation of the compound of the formula (I) of the present invention can be carried out in a continuous or astringent synthetic route. The synthesis of the present invention is shown in the following general scheme. The techniques required for the reaction and purification of the resulting product are known to those skilled in the art. Where a mixture of mirror image or non-image isomers is produced during the reaction, such image isomers or non-image isomers may be by methods described herein or by methods known to those skilled in the art ( For example, (for palmar) chromatography or crystallization) to separate. The substituents and indices used in the following description of such methods have the meanings given herein.

The following abbreviations are used herein: BOC = third butoxycarbonyl, BuLi = butyl lithium, CDI = 1, 1-carbonyldiimidazole, DBU = 2,3,4,6,7,8,9,10 - octahydro-pyrimido[1,2-a]azepine, DCE=1,2-dichloroethane, DCM=dichloromethane, DIAD=diisopropyl-azocarboxylate, DIBALH=di- Isobutyl aluminum hydride, DCC=N,N'-bis(cyclohexylcarbodiimide)methane, DMA=N,N-dimethylacetamide, DMAP=4-dimethylaminopyridine, DMF= N,N-dimethylformamide, EDCI=N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, eq.=eq., HATU=hexafluorophosphoric acid O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium, HPLC=high performance liquid chromatography, HOBT=1-hydroxybenzotriazole, Huenig's base = iPr ₂ NEt = N-ethyl diisopropylamine, LAH = lithium aluminum hydride, LDA = lithium diisopropylamide, NHS = N-hydroxy-succinimide, PG = protecting group, Red -Al = sodium bis(2-methoxyethoxy)aluminum hydride, RT = room temperature, TBME = third butyl methyl ether, TBTU = tetrafluoroboric acid O-benzotriazol-1-yl-N, N , N', N'-tetramethyl-urea, TEA = Et ₃ N = triethylamine, TFA = trifluoroacetic acid, THF = tetrahydrofuran, quant. = quantitative.

The synthesis of the compound of formula I can be accomplished according to Scheme 1. The α-amino-aldehyde 1 which is suitably protected (for example, protected by a BOC group) is reacted with a Reformatsky reagent derived from ethyl 2 -bromo-2,2-difluoroacetate 2 to Amino-hydroxy-ester 3 is provided under chelation control (Scheme 1, step a). The latter is converted to the indoleamine 5 by treatment with the essential amine 4 at elevated temperature (usually in boiling methanol) (Scheme 1, step b). Conventional deprotection (in the case of a BOC group, the free amine 6 is delivered with, for example, TFA or anhydrous HCl in dioxane) (Scheme 1, step c), which can then be combined with building block 7 (about Its synthesis, see below) is coupled under standard peptide coupling conditions (for example, in HATU or TBTU) with a suitable base (eg, Huenig's base or TEA) in an inert solvent (eg, DMF) to provide intermediate 8 ( Option 1, step d). Alternatively, the amine 6 NHS- ester and 7 'Xiaoteng - the Bowman (Schotten Baumann) conditions in the presence of (e.g.) a mixture of THF, DME and water in a mild base (such as NaHCO ₃₎ coupling of the same to yield electrode Intermediate 8 (Scheme 1, step d). Finally, the oxidation of the iodosane in an inert solvent such as DCM (eg, with Dess Martin Siodane) produces the final target molecule I. The starting aldehyde 1 which is easy to racemize (in the case where one of R ² or R ³ is hydrogen) is prepared from the corresponding Weinreb decylamine as described in the literature by using LAH reduction and used directly In the next step (J. Med. Chem. 1992, 35, 4795-4808).

The building block 7 used in Scheme 1 can be synthesized as summarized in Scheme 2. A suitable commercially available amino acid 1 is converted to the corresponding bis-alkylated derivative 2 by treatment with two equivalents of trimethylchloromethane and a tertiary amine (for example, TEA or Huenig's base) (Scheme 2, Step a) Or, if R ^{7 is} not equal to hydrogen, one equivalent of trimethylchlorodecane is used. The latter nitrogen is then deuterated by treatment with acid 3 and a conventional coupling reagent such as HATU or TBTU and a suitable base (eg, Huenig's base) in an inert solvent such as DCM to yield the desired intermediate ( Option 2, step b).

The NHS-ester 7' of Scheme 1 can be obtained by treating 7 with 1-hydroxypyrrolidine-2,5-dione, EDC and pyridine in DCM at ambient temperature.

In another synthetic variant, as outlined in Scheme 3, the intermediate 6 of Scheme 1 is first treated with an amino acid 1 suitably protected (eg, protected with a BOC group) under standard conditions by using a coupling reagent (such as TBTU) , HATU, EDCI/HOBT, etc.) and a base such as Huenig's base or TEA are treated in an inert solvent such as N,N-dimethylformamide to prolong to produce 2 (Scheme 3, Step a) . After deprotection affords 3 , for example by treatment with TFA or anhydrous HCl in dioxane (Scheme 3, step b), the latter with NHS-ester 4 under Schottten-Baumann conditions in, for example, THF, a mixture of DME and water in a base mild (such as NaHCO ₃₎ the presence of a coupling, to produce penultimate intermediate 5 (scheme 3, step c). The target molecule I is ultimately delivered by oxidation of the free alcohol (e.g., with Dess Martin Siodane) in an inert solvent such as DCM. In yet another embodiment, 3 can also be coupled with the free acid 4' under classical peptide coupling conditions as described above.

The acid 3 in Scheme 2 (same as the acid 4' in Scheme 3) is commercially available or can be prepared as follows: where the carboxylic acid derivative belongs to the family of beta phenyl substituted phenylpropionic acid derivatives These intermediates can be prepared by various conditions, and examples of such conditions can be the following general synthetic procedures, referred to herein as "Grignard route" and "Frieder-Quaff "Friedel-Crafts route" (Scheme 4) and the preferred "Michael condensation route" (Scheme 5). Those skilled in the art will recognize that such compounds can also be made by variations in such procedures.

If desired, the substituted phenylcinnamic acid 1 and the phenyl-grenical derivative 2 are optionally used in the presence of a catalytic amount of CuI in a solvent such as diethyl ether and/or THF and preferably at -10 ° C to 0 ° C. The reaction is carried out in the temperature range to produce a β-phenyl substituted phenylpropionic acid compound 3 (Scheme 4, step a). However, the yield is usually low and the purification is cumbersome. Alternatively, the very identical substituted phenylcinnamic acid 1 and anisole 4 are reacted in the presence of a Brönstedt acid such as p-toluenesulfonic acid at a temperature ranging from about 50 ° C to 150 ° C (preferably about 80 ° C). To produce a β-phenyl substituted methoxyphenylpropionic acid derivative 5 (Scheme 4, step b).

In a preferred alternative (Scheme 5), the aromatic aldehyde derivative 1 is treated with an alkyl 2 -cyanoacetate 2 (preferably ethyl 2-cyanoacetate) in a base such as sodium hydroxide or potassium hydroxide. Condensation in the presence of a solvent such as EtOH and at about 0 ° C to room temperature to provide cyano-phenyl-cinnamate 3 (Scheme 5, step a); only one stereoisomer is formed, However, it is not related to the synthesis result. Subsequent to the use of phenylmagnesium derivative 4 in the presence of a catalytic amount of CuI in a solvent such as Et ₂ O and/or THF and at a temperature in the range of preferably -10 ° C to 0 ° C to produce compound 5 (Scheme 5, step b). Finally, under the acidic conditions, for example, thorough hydrolysis and decarboxylation of a mixture of acetic acid and sulfuric acid contained in water at a temperature ranging from 100 ° C to 120 ° C (preferably about reflux) produces the desired racemization. Β-phenyl substituted phenylpropionic acid derivative 6 (Scheme 5, step c). The separation of the respective mirror image isomers can be converted to NHS-ester 7 by treatment with 1-hydroxypyrrolidine-2,5-dione, EDC and pyridine contained in DCM at ambient temperature (Scheme 5) , step d), followed by palmar HPLC to complete. These active esters 4 (in pure palm or racemic form) can also be used as reagent 4 in Scheme 3.

In the case where the carboxylic acid 3 in Scheme 2 (same as the acid 4' in Scheme 3) belongs to the family of β-phenoxyphenylpropionic acid derivatives, such intermediates can be prepared by various conditions, An example of such conditions can be the general synthetic procedure outlined below (Scheme 6): the addition of a commercially available allyl genomic reagent to the THF in a temperature range of preferably -78 ° C to 0 ° C under standard conditions The benzaldehyde 1 is suitably substituted to produce benzyl alcohol 2 (Scheme 6, step a). Subsequent Mitsuno reaction between the latter and a suitable phenol derivative 3 using, for example, DIAD and triphenylphosphine as reagents in a solvent such as THF and at a temperature ranging from 0 ° C to room temperature Ether 4 (Scheme 6, step b). By means of, for example, a mixture of sodium periodate and potassium permanganate in the presence of a base such as potassium carbonate in a solvent mixture such as t-BuOH/water and preferably at a temperature ranging from 0 ° C to room temperature Oxidative cleavage of the terminal olefins carried out ultimately produces the desired β-substituted phenoxyphenylpropionic acid derivative 5 (Scheme 6, step c).

The β-aryloxycarboxylic acid 5 of Scheme 6 can be made in an optically pure form in a similar manner by using pure p-palmitic benzyl alcohol 2 in a known light-diffusing process starting with clean inversion. This building block can be easily prepared as outlined in Scheme 7 by allowing Weinreb amide 1 and a commercially available allyl genomic reagent in THF/Et ₂ O at a temperature ranging from -20 ° C to ambient temperature. Reaction to produce ketone 2 (Scheme 7, step a). Mirror-selective reduction using (+)-diisopinyl chloroborane 3 in THF at a temperature ranging from -50 ° C to ambient temperature provides (R)-benzyl alcohol 4 (Scheme 7, step b, J) . Org. Chem. 2002, 67, 9192-9199). The calendering reaction using phenol 5 as above produces (S)-aryl-ether 6 (Scheme 7, step c) which is then oxidatively cleaved to (S)-acid 7 (as described above) (Scheme 7, step d ). Other mirror image isomers can also be readily obtained by relying on the (-)-diisopinyl chloroborane enantiomer-3.

A further embodiment of the invention is a process for the preparation of a compound of formula (I) as defined above, which process comprises: a) reacting a compound of formula (III) with a compound of formula (IV),

The reaction system (specifically) in the presence of a base, more specifically in the presence of sodium carbonate, in a solvent such as DME, THF and water or a mixture thereof at 0 ° C to room temperature, in particular It is carried out at room temperature.

Then b) reacting the compound of formula (II) under oxidizing conditions

The reaction system (specifically) in 1,1,1-triethoxymethoxy-1,1-dihydro-1,2-phenyliodonium-3(1H)-one (Dess-Martin periodinane) In the presence of (Dess-Martin periodane), it is carried out in a solvent similar to DCM at 0 ° C to room temperature.

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are as defined herein.

A further object of the invention is a compound according to formula (I) as described herein for use as a therapeutically active substance.

Likewise, the object of the invention is a pharmaceutical composition comprising a compound according to formula (I) as described herein and a therapeutically inert carrier.

The object of the present invention is a compound according to formula (I) as described herein for ocular diseases, in particular HtrA1-mediated eye diseases, more particularly wet or dry age-related macular degeneration, map-like atrophy, diabetic retina Use in the treatment or prevention of lesions, retinopathy of prematurity or polypoidal choroidal vasculopathy.

In a particular embodiment, a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof, for use in wet or dry age-related macular degeneration, atrophy of the map, diabetic retinopathy, retinopathy of prematurity or polyp Treatment or prevention of choroidal vasculopathy.

The invention also relates to the preparation of a compound according to formula (I) as described herein for the preparation of wet or dry age-related macular degeneration, map-like atrophy, diabetic retinopathy, retinopathy of prematurity and polypoid choroidal vasculopathy. Use in a therapeutic or prophylactic agent.

A further object of the invention is a method for the treatment or prevention of wet or dry age-related macular degeneration, map-like atrophy, diabetic retinopathy, retinopathy of prematurity and polypoidal choroidal vasculopathy, wherein the method comprises As with the effective amount A compound according to formula (I) is described.

A further embodiment of the invention is a compound according to formula (I) as described herein, which is produced according to any of the methods as described herein.

Analysis program Protein purification for enzymatic analysis

The human HtrA1 protein comprising the catalytic domain from the amino acids Asp161 to Pro480 and the PDZ domain was rendered as a 6xHis-SUMO-tagged N-terminal fusion protein in BL21(DE3) cells. The transformed cells were grown in LB medium at 37 ° C until the optical density at 600 nm was between 0.6 and 0.8. Then, the temperature was lowered to 18 ° C and recombinant protein production was induced by adding IPTG to a final concentration of 250 mM. The fermentation was carried out overnight at 18 °C.

The protein was purified to homogeneity following a four-step procedure. 40 g of cells were suspended in the following materials: 50 mM HEPES pH 7.8, 250 mM NaCl, 10 mM MgCl ₂ , 0.35% CHAPS, 10% glycerol (containing 20 labels per liter of complete protease inhibitor (Roche) without EDTA and 30 mg/ l DNase (DNAse) and RNase (RNAse)). The cells were disrupted by a single pass through a 750 bar homogenizer and then centrifuged at 20,000 xg for 30 minutes. The clarified supernatant was applied to a three-fold 5 ml HisTrap column (GE Healthcare) equilibrated in 50 mM HEPES pH 7.8, 500 mM NaCl, 0.35% CHAPS, 10% glycerol. After washing with increasing concentrations of imidazole (20 mM, 40 mM, 50 mM), the HtrA1 fusion protein was lysed in a 10 to 100% linear gradient of the same buffer containing 500 mM imidazole. The fractions containing HtrA1 were combined, concentrated and then applied to a Superdex S200 preparation grade (XK26/100-GE Healthcare) equilibrated in 50 mM ethanolamine pH 9.6, 500 mM NaCl, 0.35% CHAPS, 10% glycerol, 0.02% sodium azide. On the pipe column. To cleave the SUMO fusion protein and release the active HtrA1, the pooled fractions from size exclusion chromatography were spiked with SUMO protease (Life Technologies) and incubated for approximately 20 hours at room temperature. Chromatography on a Superdex S200 preparative grade (XK26/100-GE Healthcare) column equilibrated in 50 mM ethanolamine pH 9.6, 500 mM NaCl, 0.35% CHAPS, 10% glycerol, 0.02% sodium azide HtrA1 was isolated from the reaction solution. The fractions containing active HtrA1 were combined and concentrated. Following the above strategy, 150 mg of HtrA1 (catalytic domain/PDZ construct) can be purified. A protein of >98% purity can be obtained as indicated by RP-HPLC and SDS-PAGE.

HtrA1 inhibition assay

The enzyme activity was measured by observing an increase in the fluorescence intensity caused by cleavage of a peptide containing a fluorophore whose emission was suspended in the intact peptide.

Analytical buffer: 500 mM Tris pH 8.0, 200 mM NaCl, 0.025% CHAPS, 0.005% BSG

Enzyme: Human HtrA1 Cat-PDZ, final concentration 1nM

Substance: Mca-Ile-Arg-Arg-Val-Ser-Tyr-Ser-Phe-Lys(Dnp)-Lys, final concentration 500 nM (from Innovagen Cat: SP-5076-1, Lot: 89584.02)

Mca=(7-methoxycoumarin-4-yl)ethenyl

Dnp=2,4-dinitrophenyl

Final volume: 51μl

Excitation 320nm, emission 390nm

After pre-incubation of the HtrA1 protease with the compound for 30 minutes, the substrate was added to the wells and the initial RFU was measured. Once cultured for 2 hours at room temperature, the enzyme cleaves the substrate, thereby releasing the fluorescent Mca-peptide conjugate and measuring the final RFU value. The presence of an inhibitor results in a reduction in the final RFU.

For analysis, the ΔRFU was calculated as the RFU _end- RFU _start , and then the percent inhibition was calculated using the following formula: PCT_inhibition=100-100* (ΔRFU _compound -ΔRFU _blank )/(ΔRFU _{negative control} -ΔRFU _Blank )

Negative control protease and substrate and DMSO

Blank no protease negative control

The compound serves as a negative control for the test compound at the desired concentration

IC ₅₀ is determined using a 4-point Hill-fit equation, where x = concentration of test compound

A = curve is pushed outside the effector concentration equal to 0

B = curve is pushed outside the effector concentration equal to infinity

C = concentration at the inflection point of the sigmoid curve (IC ₅₀ )

D = Hill coefficient of the slope at the inflection point of the fitted curve

As a reverse screen, the compounds were added to the protease-substrate reaction mixture after only 2 hours of incubation, and when all of the substrates were turned over, to identify the autofluorescence or absorption compound for a given false positive hit.

As described in this document of formula (I) compound and a pharmaceutically acceptable salt or ester thereof having IC ₅₀ values of between 1000μM, the specific compound having IC ₅₀ values of 0.0005μM to 500μM in between in 0.00001μM, other specific compound having IC ₅₀ values of between 50μM, more specifically compounds having IC ₅₀ values of between 0.0005 and 5μM in the 0.0005μM. These results have been obtained by using the enzyme assay described above.

The compound of the formula (I) and a pharmaceutically acceptable salt thereof can be used as a medicament (for example, in the form of a pharmaceutical preparation). Such pharmaceutical preparations may be administered internally, for example, orally (for example, in the form of lozenges, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (for example, nasal sprays). Form), rectal (eg, in the form of a suppository) or ocular (eg, in the form of a solution, ointment, gel, or water soluble polymeric insert). However, the administration can also be effected parenterally, such as intramuscularly, intravenously or intraocularly (for example, in the form of a sterile injectable solution).

The compound of the formula (I) and a pharmaceutically acceptable salt thereof may be processed with a pharmaceutically inert inorganic or organic adjuvant to prepare a tablet, a coated tablet, a sugar-coated tablet, a hard gelatin capsule, an injection solution or a topical formulation; lactose may be used. Corn starch or a derivative thereof, mica, stearic acid or a salt thereof, for example, an adjuvant for a tablet, a sugar-coated tablet and a hard gelatin capsule.

Adjuvants suitable for use in soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid materials and liquid polyols.

Adjuvants suitable for use in the manufacture of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, and the like.

Adjuvants suitable for injectable solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

Adjuvants suitable for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like.

Adjuvants suitable for topical eye formulations are, for example, cyclodextrins, mannitol or many other carriers and excipients known in the art.

In addition, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying osmotic pressure, buffers, masking Agent or antioxidant. They may also contain other therapeutically valuable substances.

The dosage can vary over a wide range and will (of course) be adapted to individual needs in each particular case. In general, in the case of oral administration, a daily dose of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (for example, about 300 mg per person) (divided into preferably 1 to Three individual doses, which may be, for example, of the same amount, should be appropriate. In the case of topical administration, the formulation may contain from 0.001% to 15% by weight of the agent, and the desired dose (which may range from 0.1 to 25 mg) may be administered by a single daily or weekly dose or Dosing by multiple doses per day (2 to 4) or by multiple doses per week. In the case of parenteral administration (such as intramuscular, intravenous or intraocular), the formulation may contain 0.001% by weight to 15% by weight of the agent, and the required dose (which may be between 0.1 and 25 mg) may be administered by a single dose per day, week or month or by multiple doses per day (2 to 4) or By multiple doses per week or monthly. However, it should be understood that when indicated, the upper or lower limits given herein may be exceeded.

The invention is illustrated below by way of example without limitation.

Where the preparative examples are obtained as a mixture of mirror image isomers, the pure mirror image isomers may be by methods described herein or by methods known to those skilled in the art such as, for example, the palm layer. Obtained by precipitation or crystallization.

Instance

All examples and intermediates were prepared under a nitrogen atmosphere unless otherwise specified.

Intermediate Ia

3-(3,5-dichlorophenyl)-3-(4-methoxyphenyl)propionic acid

[A](Z)-2-cyano-3-(3,5-dichlorophenyl)prop-2-enoic acid ethyl ester

In a 50 mL pear-shaped flask, 3,5-dichlorobenzaldehyde (1.5 g, 8.57 mmol, Eq: 1) and ethyl 2-cyanoacetate (2.91 g, 2.74 ml, 25.7 mmol, Eq: 3) and EtOH were combined. (10ml) to produce a colorless solution and some residual aldehyde (supersaturated); add sodium hydroxide particles (171 Mg, 4.29 mmol, Eq: 0.5) and the mixture was stirred at ambient temperature and isolated from water; TLC after 1.5 hours indicated that the initial aldehyde had completely disappeared. After 2 hours, the reaction mixture was poured onto EtOAc / EtOAc EtOAc (EtOAc) Object, which is designated as a Z configuration without being proven. If desired, more product can be separated from the mother liquor by column chromatography.

[B]ethyl 2-cyano-3-(3,5-dichlorophenyl)-3-(4-methoxyphenyl)propanoate

Copper (I) iodide (10.6 mg, 55.5 μmol, Eq: 0.1) and diethyl ether (5 ml) were combined in a 25 mL three-necked flask to give an off-white suspension. Add (4-methoxyphenyl)magnesium bromide 0.5 M (2.22 ml, 1.11 mmol, Eq: 2) in THF at 0 ° C, and then add dropwise to tetrahydrofuran (4 ml) A solution of (Z)-2-cyano-3-(3,5-dichlorophenyl)acrylate (150 mg, 555 μmol, Eq: 1) obtained above. The reaction mixture was stirred at 0 °C. TLC after 1 hour showed the reaction was completed.

The reaction mixture (brown solution) was cooled to -75 ° C and quenched with 5 mL of saturated NH ₄ Cl. After 5 minutes the cooling bath was removed and the mixture allowed to warm to room temperature. Extracted with EtOAc, washed with H ₂ O / NaCl solution was washed, dried and concentrated in vacuo, followed by flash chromatography (silica gel, 20g, in heptane of 17% EtOAc) produced 168mg of the title compound as a colorless oil; MS :376.2(MH) ^- .

[C]3-(3,5-Dichlorophenyl)-3-(4-methoxyphenyl)propionic acid

Ethyl 2-cyano-3-(3,5-dichlorophenyl)-3-(4-methoxyphenyl)propanoate (162 mg, 428 μmol, Eq: 1), Concentrated H ₂ SO ₄ (1 ml) was added to a mixture of acetic acid (2 ml) and H ₂ O (1 ml). The reaction mixture was stirred at 105 ° C for 23 hours. The heating was stopped and the reaction mixture was cooled to room rt, poured over EtOAc EtOAc (EtOAc) The organic layer was washed with H ₂ O / NaCl solution was washed concentrated in vacuo and dried over Na ₂ SO ₄ and. The crude material was purified by flash chromatography (silica gel, 20g, in 30% of heptane to 80% EtOAc) was purified to yield 113mg of the title product as a colorless oil; MS: 649.3 (2M-H ) -.

Can be prepared very similarly:

Intermediate Ib

3-(3,4-dichlorophenyl)-3-(4-methoxyphenyl)propionic acid

A colorless oil, MS: 323.1 (MH) ^- .

Intermediate Ic

3-(3,4-dichlorophenyl)-3-phenylpropionic acid

Light brown oil, MS: 589.2 (2M-H) ^- .

Intermediate Id

3-(3,5-dichlorophenyl)-3-phenylpropionic acid

White semi-solid; MS: 589.2 (MH) ^- .

Intermediate Ie

3-(4-bromophenyl)-3-phenylpropionic acid

Grayish white semi-solid; MS: 609.2 (2M-H) ^- .

Intermediate If

3-(3,5-difluorophenyl)-3-(4-methoxyphenyl)propionic acid

Light yellow oil; MS: 291.1 (MH) ^- .

Intermediate Ig

3-(3-chlorophenyl)-3-phenylpropionic acid

A colorless oil, MS: 259.1 (M-H).

Intermediate IIa

3-(3,4-dichlorophenyl)-3-phenoxypropionic acid

[A] 1,2-dichloro-4-(1-phenoxybut-3-enyl)benzene

In a 25 mL three-necked flask, 1-(3,4-dichlorophenyl)but-3-en-1-ol (267 mg, 1.23 mmol, Eq: 1) and DCM (12 ml) were combined to give a colorless solution. Phenol (127 mg, 1.35 mmol, Eq: 1.1) and triphenylphosphine (419 mg, 1.6 mmol, Eq: 1.3) were added and the reaction mixture was cooled to 0 °C. DIAD (323 mg, 311 μl, 1.6 mmol, Eq: 1.3) was added over 20 minutes at +1.5 <T °C> + 3 °C. The reaction mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 1 hour. The crude reaction mixture was concentrated in EtOAc EtOAc (EtOAc:EtOAc. MH) ^- .

[B]3-(3,4-dichlorophenyl)-3-phenoxypropionic acid

A solution of sodium periodate (1.69 g, 7.92 mmol, Eq: 9) in water (35 ml) with potassium permanganate (55.6 mg, 352 μmol, Eq: 0.4), potassium carbonate (1.82 g, 13.2 mmol, Eq) :15) and tBuOH (4ml) treatment. The 1,2-dichloro-4-(1-phenoxybut-3-en-1-yl)benzene obtained above in tBuOH (9 ml) was slowly added to this mixture at ~+5 °C. A solution of (258 mg, 880 μmol, Eq: 1) and the resulting mixture was stirred at room temperature for 3 hours, and LC-MS and TLC after 3 hours indicated some of the remaining starting material. A solution of potassium permanganate (55.6 mg, 352 μmol, Eq: 0.4) in 5 ml of H ₂ O was added and the reaction mixture was further stirred at room temperature for 1 hour. LC-MS and TLC now show that the reaction is complete. This mixture was treated with ethylene glycol (1.11 g, 1 ml, 17.9 mmol, Eq: 20.4), stirred for 1 hour and acidified to pH 2 with 25% HCl at 0 °C. The brown solid obtained was filtered off and the filtrate was extracted with AcOEt (2x). The organic layer was washed with brine, then dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 20g, in 20% of heptane to 100% EtOAc) to afford the title acid 146mg of a pale yellow oil; MS: 621.2 (2M-H ) -.

Prepared in a very similar manner using suitable commercially available building blocks:

Intermediate IIb

3-(4-chlorophenoxy)-3-(3,4-dichlorophenyl)propanoic acid

Yellow gum, MS: 689.1 (2M-H) ^- .

Intermediate IIc

(3S)-3-(3-chlorophenoxy)-3-phenylpropionic acid

[A](1R)-1-phenylbut-3-en-1-ol

In a 50 mL four-necked flask, (+)-diisopinyl chloroborane (3.79 g, 11.8 mmol, Eq: 1.2) and tetrahydrofuran (10 ml) were combined to give a colorless solution. A solution of 1-phenylbut-3-en-1-one (1.8 g, 9.85 mmol, Eq: 1) in tetrahydrofuran (5 ml) was added dropwise at -50 °C. The reaction mixture was allowed to slowly warm to room temperature over the weekend. The crude reaction mixture was concentrated in vacuo and then concentrated at 40 ° C under high pressure (hv) for 10 min to remove (-) a-decene formed during the reaction. The remaining residue was taken up in EtOAc (EtOAc) (EtOAc) The mixture was stirred for 5 minutes at room temperature and transferred to a separatory funnel. The aqueous layer was back-extracted with tBuOMe, the organic layer was washed with brine, combined, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by flash chromatography (EtOAc EtOAc EtOAc EtOAc EtOAc Ethanol/isopropanol) confirmed optical purity of >>95%.

[B]1-chloro-3-[(1S)-1-phenylbut-3-enyloxy]benzene

In a 50 mL three-necked flask, (R)-1-phenylbut-3-en-1-ol (300 mg, 2.02 mmol, Eq: 1) and dichloromethane (20 ml) were combined to give colorless. Solution. 3-Chlorophenol (286 mg, 230 μl, 2.23 mmol, Eq: 1.1) and triphenylphosphine (690 mg, 2.63 mmol, Eq: 1.3) were added in that order. The reaction mixture was cooled to 0 ° C and DIAD (532 mg, 512 μl, 2.63 mmol, Eq: 1.3) was added while maintaining the temperature below 5 ° C for 10 minutes, and the reaction was allowed to proceed at 0 ° C for 30 minutes at room temperature Carry out for 1 hour. The crude reaction mixture was then concentrated in EtOAc (mjqqqqq

[C](3S)-3-(3-chlorophenoxy)-3-phenylpropionic acid

A solution of sodium periodate (1.65 g, 7.72 mmol, Eq: 9) in water (30 ml) with potassium permanganate (54.2 mg, 343 μmol, Eq: 0.4), potassium carbonate (1.78 g, 12.9 mmol, Eq) :15) and tBuOH (4ml) treatment. (S)-1-Chloro-3-((1-phenylbut-3-en-1-yl)oxy)benzene (222 mg, obtained above) was slowly added to this mixture at ~+5 °C. 858 μmol, Eq: 1) A solution in tBuOH (9 ml) and the mixture was stirred at room temperature for 3 hours. After 3 hours, LC-MS and TLC showed that some starting material was still present. Therefore, another solution of potassium permanganate (54.2 mg, 343 μmol, Eq: 0.4) in 5 ml of H ₂ O was added and the reaction mixture was further stirred at room temperature for 1 hour; LC-MS and TLC indicated that the reaction was completed. . The reaction mixture was treated with EtOAc (1. <RTI ID=0.0></RTI></RTI><RTIgt; The brown solid obtained was filtered off and the filtrate was extracted with AcOEt (2x). The organic layer was washed with brine, then dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 50g, in 20% of heptane to 100% EtOAc) was purified to give the title acid 151mg of a pale yellow ^{oil; MS: 275.1 (MH) -} .

Intermediate IId

3-(3-chlorophenoxy)-3-(3,4-dichlorophenyl)propanoic acid

Intermediate IIb Similarly prepared using 3-chlorophenol instead of 4-chlorophenol to build a block, as a pale yellow waxy solid; MS: 687.0 (2M-H ) -.

Intermediate IIe

(3R)-3-(3-chlorophenoxy)-3-phenylpropionic acid

Preparation of intermediate IIc Similarly, but using (-) - camphene diisocyanate pine chloride borane as the reducing agent, as a colorless ^{oil; MS: 275.1 (MH) -} .

Intermediate IIf

(3S)-3-(4-chlorophenoxy)-3-(3,4-dichlorophenyl)propionic acid

Similar to the preparation of intermediate IIc , but starting the reaction sequence with 1-(3,4-dichlorophenyl)but-3-en-1-one and 4-chlorophenol as the building block for the light-delay reaction, grayish white Solid; MS: 687.1 (2M-H) ^- .

Intermediate IIg

3-(3-chlorophenoxy)-3-(5-chloropyridin-3-yl)propionic acid

Prepared similarly to intermediate IIb, but using 1-(5-chloropyridin-3-yl)but-3-en-1-ol and 3-chlorophenol as building blocks, respectively, as yellow oil; MS: 310.1 (MH) ^- .

Intermediate IIh

3-(3-chlorophenyl)-3-pyridin-3-yloxypropionic acid

Prepared similarly to intermediate IIb, but using 1-(3-chlorophenyl)but-3-en-1-ol and pyridin-3-ol as the building blocks, respectively, as a white solid; MS: 276.2 (MH) ^- .

Intermediate IIi

3-(3-chlorophenyl)-3-(5-chloropyridin-3-yl)oxypropionic acid

Prepared similarly to intermediate IIb, but using 1-(3-chlorophenyl)but-3-en-1-ol and 5-chloropyridin-3-ol as building blocks, respectively, as a yellow foam; MS: 312.0 (MH) ) ^- .

Intermediate IIIa

N-[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexane- 3-yl]carbamic acid tert-butyl ester

[A](3R,4S)-4-Amino-2,2-difluoro-3-hydroxy-5-methylhexanoic acid ethyl ester

(S)-(3-Methyl-1-oxobutan-2-yl)carbamic acid tert-butyl ester (2.01 g, 9.99 mmol, Eq: 1) and 2 in THF (15 ml) - A solution of ethyl bromo-2,2-difluoroacetate (6.08 g, 3.84 ml, 30 mmol, Eq: 3) was added dropwise to activated zinc (1.96 g, 30 mmol, Eq: 3) in THF (65 ml) In the suspension. After that, the reaction was refluxed for 2 hours. Remove the heat source and allow the reaction to cool to ambient temperature. The reaction mixture was poured in 15mL 1N KHSO ₄ and extracted with EtOAc (2 x 25mL). The organic layers were combined, washed with brine, dried over Na ₂ CH ₄ The crude material was purified by flash chromatography eluting elut elut elut elut elut elut

[B]N-[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino) Hex-3-yl]carbamic acid tert-butyl ester

(3R,4S)-4-Amino-2,2-difluoro-3-hydroxy-5-methylhexanoic acid ethyl ester (191.4 mg, 588 μmol, Eq: 1), 3, 3 , a mixture of 3-trifluoropropan-1-amine (333 mg, 2.94 mmol, Eq: 5) and N,N-diisopropylethylamine (380 mg, 514 μl, 2.94 mmol, Eq: 5) was refluxed in 5 mL MeOH overnight. TLC after 17 hours showed the reaction was completed. The reaction volume was reduced in vacuo and EtOAc was added to the residue. The organic layer was washed with brine (3x), concentrated in vacuo and dried over Na ₂ SO ₄ and. The crude material was purified by flash chromatography (silica gel, 20g, in 15% of heptane to 50% EtOAc) was purified to yield 180mg of the title compound as a white ^{foam; MS: 391.4 (MH) -} .

[C](3R,4S)-4-Amino-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexylamine

In a 25 mL round bottom flask, the N-[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2) prepared above was combined. , 2-trifluoroethylamino)hexane-3-yl]carbamic acid tert-butyl ester (177 mg, 451 μmol, Eq: 1) and 1,4-dioxane (6 ml) to give a colorless solution.

HCl 4M in dioxane (2.25 ml, 9 mmol, Eq: 20) was added and the mixture was stirred at room temperature overnight. The crude reaction mixture was concentrated in vacuo and carefully dried under high pressure and used directly in the next step.

Prepared in a very similar manner using the appropriate commercially available amine component:

Intermediate IIIb

(3R,4S)-4-amino-2,2-difluoro-3-hydroxy-5-methyl-N-(3,3,3-trifluoropropyl)hexylamine

A colorless oil, MS: 293.2 (M+H) ⁺ .

Intermediate IIIc

(3R,4S)-4-amino-2,2-difluoro-3-hydroxy-5-methyl-N-(2-morpholin-4-ylethyl)hexylamine

White foam, MS: 310.3 (M+H) ⁺ .

Intermediate IIId

(3R,4S)-4-amino-2,2-difluoro-3-hydroxy-5-methyl-N-(2-phenylethyl)hexylamine

Light yellow oil, MS: 301.3 (M+H) ⁺ .

Intermediate IIIe

(3R,4S)-4-amino-N-ethyl-2,2-difluoro-3-hydroxy-5-methylhexylamine

It is a colorless oil.

Intermediate IIIf

(3R,4S)-4-amino-2,2-difluoro-3-hydroxy-5-methyl-N-propylhexylamine

It is a colorless oil.

Intermediate IIIg

(3R,4S)-4-amino-2,2-difluoro-3-hydroxy-5-methyl-N-(2-methylpropyl)hexylamine

It is white foam.

Intermediate IIIh

(3R,4S)-4-amino-N-(2,2-dimethylpropyl)-2,2-difluoro-3-hydroxy-5-methylhexylamine

It is white foam.

Intermediate IVa

(2S)-2-[3-(3-chlorophenyl)propanylamino]-3-phenylpropionic acid

(S)-2-Amino-3-phenylpropionic acid (1 g, 6.05 mmol, Eq: 1) and DCM (30 mL) were combined to give a white suspension in a 50 mL round bottom flask; N was added at 0 °C , N-diisopropylethylamine (2.35 g, 3.17 ml, 18.2 mmol, Eq: 3) and trimethylchloromethane (1.38 g, 1.62 ml, 12.7 mmol, Eq: 2.1) and stirred at room temperature The reaction was allowed to proceed for 15 minutes to give a colorless solution.

In a second 250 mL round bottom flask, 3-(3-chlorophenyl)propionic acid (1.12 g, 6.05 mmol, Eq: 1) and DMF (30 ml) were combined to give a colorless solution; N,N-diisopropyl Ethylethylamine (939 mg, 1.27 ml, 7.26 mmol, Eq: 1.2) and TBTU and the mixture was stirred for 20 min. The solution prepared above from "Flask 1" was added and the reaction was allowed to proceed for an additional 3 hours.

It was then poured into H ₂ O and extracted with DCM (2×). The organic layers were combined, on _{4 2} SO ₄ solution and with KHSO Na brine dried and concentrated in vacuo.

Purification by flash chromatography (EtOAc, EtOAc (EtOAc:EtOAc) ⁺ .

Prepared in a very similar manner using commercially available building blocks or suitable intermediates I:

Intermediate IVb

(2S)-2-[3-(3,5-Dichlorophenyl)propanylamino]-3-phenylpropionic acid

An off-white solid; MS: 366.1 (M + H ) +.

Intermediate IVc

(2S)-2-[[2-(3-chlorophenoxy)ethinyl]amino]-3-phenylpropionic acid

White solid; MS: 334.2 (M+H) ⁺ .

Intermediate IVd

(2S)-2-[[2-(3,4-Dichlorophenoxy)ethinyl]amino]-3-phenylpropionic acid

White solid; MS: 368.1 (M+H) ⁺ .

Intermediate IVe

(2S)-2-[3-(3,4-dichlorophenyl)propanylamino]-3-phenylpropionic acid

An off-white solid; MS: 366.1 (M + H ) +.

Intermediate IVf

(2S)-3-(4-chlorophenyl)-2-[3-(3,4-dichlorophenyl)propanylamino]propionic acid

An off-white solid; MS: 400.1 (M + H ) +.

Intermediate IVg

(2S)-2-[3-(3,4-Dichlorophenyl)propanylamino]-3-(3,4-dimethoxyphenyl)propanoic acid

An off-white solid; MS: 426.2 (M + H ) +.

Intermediate IVh

(2S)-3-(3,4-dichlorophenyl)-2-[3-(3,4-dichlorophenyl)propanylamino]propionic acid

An off-white solid; MS: 434.1 (M + H ) +.

Intermediate IVi

(2S)-2-[[2-(3,5-Dichlorophenoxy)ethenyl]amino]-3-(3,4-dichlorophenyl)propanoic acid

An off-white ^{solid; MS: 434.1 (MH) -} .

Intermediate IVj

(2S)-3-(4-chlorophenyl)-2-[[2-(3,5-dichlorophenoxy)ethinyl]amino]propionic acid

An off-white solid; MS: 402.2 (M + H ) +.

Intermediate IVk

(2S)-2-[[2-(3,5-Dichlorophenoxy)ethenyl]amino]-3-(3,4-difluorophenyl)propanoic acid

An off-white ^{solid; MS: 402.2 (MH) -} .

Intermediate IVl

(2S)-2-[[2-(3,5-Dichlorophenoxy)ethenyl]amino]-3-(3,4-dimethoxyphenyl)propanoic acid

An off-white solid; MS: 428.2 (M + H ) +.

Intermediate IVm

(2S)-2-[[2-(3,5-Dichlorophenoxy)ethinyl]amino]-3-phenylpropionic acid

An off-white solid; MS: 368.1 (M + H ) +.

Intermediate IVn

(2S)-2-[[2-(3,5-Dichlorophenoxy)ethinyl]amino]-2-phenylacetic acid

An off-white solid; MS: 354.0 (M + H ) +.

Intermediate IVo

(2S)-2-[[2-(3,5-Dichlorophenoxy)ethenyl]amino]-2-(4-fluorophenyl)acetic acid

An off-white solid; MS: 354.0 (M + H ) +.

Intermediate IVp

(2S)-2-[[3-(3,4-Dichlorophenyl)-3-phenylpropanyl]amino]-3-phenylpropionic acid

White foam; MS: 442.3 (M+H) ⁺ .

Intermediate IVq

(2S)-2-[[3-(3,4-Dichlorophenyl)-3-(4-methoxyphenyl)propanyl]amino]-3-phenylpropionic acid

Light yellow oil; MS: 472.2 (M+H) ⁺ .

Intermediate IVr

(2S)-2-[[(E)-3-(3,4-dichlorophenyl)prop-2-enyl]amino]-3-phenylpropionic acid

Yellow foam; MS: 364.1 (M+H) ⁺ .

Intermediate IVs

(2S)-2-[[(E)-3-(3,5-Dichlorophenyl)prop-2-enyl]amino]-3-phenylpropionic acid

Yellow oil; MS: 364.1 (M+H) ⁺ .

Intermediate Va

(2S)-2-[3-(3,4-Dichlorophenyl)propanylamino]-3-(4-methoxyphenyl)propionic acid

A] 3-(3,4-dichlorophenyl)propionic acid (2,5-di-oxypyrrolidin-1-yl) ester

In a 50 mL round bottom flask, 3-(3,4-dichlorophenyl)propionic acid (704 mg, 3.21 mmol, Eq: 1) and DCM (15 ml) were combined to give a colorless solution; then pyridine was added at 0 ° C ( 763 mg, 780 μl, 9.64 mmol, Eq: 3), EDC (862 mg, 4.5 mmol, Eq: 1.4) and 1-hydroxypyrrolidine-2,5-dione (481 mg, 4.18 mmol, Eq: 1.3) at room temperature The reaction mixture was stirred overnight and overnight LC-MS indicated the reaction was completed.

The reaction mixture was suspended with KHSO ₄ and extracted with DCM (2x). The organic layers were combined, washed with saturated NaHCO _3, brine, and concentrated in vacuo and dried over Na ₂ SO ₄ and. The crude material was purified by flash chromatography (silica gel, 70g, in 10% of heptane to 50% EtOAc) to afford 957mg of the title compound as a white solid; MS: 217.1 (M- succinimidyl acyl imino) ^- .

B] 3-(3,4-dichlorophenyl)propionic acid (2,5-di-oxypyrrolidin-1-yl) ester

In a 10 mL round bottom flask, (S)-2-amino-3-(4-methoxyphenyl)propionic acid (74.1 mg, 380 μmol, Eq: 1) and THF (1 ml) were combined to give a white suspension. ; 2,5-di-oxypyrrolidin-1-yl 3-(3,4-dichlorophenyl)propanoate (120 mg, 380 μmol, Eq: obtained above) in DME (2 ml) 1) and water (2ml) of the _{NaHCO 3 (31.9mg, 14.8μl, 380μmol} , Eq: 1), and the heterogeneous mixture was stirred vigorously. LC-MS after 5 hours showed the reaction was completed.

The mixture was poured into a KHSO ₄ and extracted with EtOAc (2x). The organic layers were combined, washed with brine, dried over Na ₂ CH ₄ The crude material was purified by flash chromatography (silica gel, 20g, 1% to 10% MeOH DCM in the) purified to yield 107mg of the title product was an off-white solid; MS: 396.1 (M + H ) +.

Prepared in a very similar manner using the appropriate commercial reagents and the necessary intermediates I or II:

Intermediate Vb

(2S)-2-[[2-(3,5-Dichlorophenoxy)ethenyl]amino]-2-(4-fluorophenyl)acetic acid

As a white ^{solid; MS: 370.1 (MH) -} .

Intermediate Vc

(2S)-2-[3-(3,4-dichlorophenyl)propanylamino]-2-phenylacetic acid

White solid; MS: 352.0 (M+H) ⁺ .

Intermediate Vd

(2S)-2-[[3-(3,4-Dichlorophenyl)-3-phenylpropanyl]amino]-2-phenylacetic acid

White foam; MS: 428.1 (M+H) ⁺ .

Intermediate Ve

(2S)-2-(4-chlorophenyl)-2-[[2-(3,5-dichlorophenoxy)ethinyl]amino]acetic acid

As a white solid; MS: 388.0 (M + H ) +.

Intermediate Vf

(2S)-2-(4-chlorophenyl)-2-[[3-(3,4-dichlorophenyl)-3-phenylpropanyl]amino]acetic acid

White foam; MS: 462.0 (M+H) ⁺ .

Intermediate Vg

(2S)-2-[[3-(3,5-Dichlorophenyl)-3-(4-methoxyphenyl)propanyl]amino]-3-phenylpropionic acid

White foam; MS: 472.2 (M+H) ⁺ .

Intermediate Vh

(2S)-3-(4-chlorophenyl)-2-[[3-(3,4-dichlorophenyl)-3-phenylpropanyl]amino]propionic acid

White foam; MS: 476.1 (M+H) ⁺ .

Intermediate Vi

(2S)-2-[[3-(4-bromophenyl)-3-phenylpropanyl]amino]-3-phenylpropionic acid

White foam; MS: 452.2 (M+H) ⁺ .

Intermediate Vj

(2S)-2-[[3-(4-bromophenyl)-3-phenylpropanyl]amino]-3-(4-chlorophenyl)propanoic acid

As a white foam; MS: 486.1 (M + H ) +.

Intermediate Vk

(2S)-2-[[3-(3,4-Dichlorophenyl)-3-phenoxypropanyl]amino]-3-phenylpropionic acid

White foam; MS: 458.0 (M+H) ⁺ .

Intermediate Vl

(2S)-2-[[3-(4-Chlorophenoxy)-3-(3,4-dichlorophenyl)propanyl]amino]-3-phenylpropionic acid

White foam; MS: 490.1 (MH) ^- .

Intermediate Vm

(2S)-2-(3,3-diphenylpropanylamino)-3-phenylpropionic acid

White foam; MS: 374.2 (M+H) ⁺ .

Intermediate Vn

(2S)-2-[[3-(3,4-Dichlorophenyl)-3-phenylpropanyl]amino]-3-(4-methoxyphenyl)propionic acid

White foam; MS: 472.2 (M+H) ⁺ .

Intermediate Vo

(2S)-2-[[3-(3,5-Difluorophenyl)-3-(4-methoxyphenyl)propanyl]amino]-3-phenylpropionic acid

White foam; MS: 440.2 (M+H) ⁺ .

Intermediate VIa

(3R,4S)-4-[[(2S)-2-Amino-2-phenylethenyl]amino]-2,2-difluoro-3-hydroxy-5-methyl-N-( 2,2,2-trifluoroethyl)hexylamine

A]N-[(1S)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6- pendantoxy-6-(2,2,2- Trifluoroethylamino)hexane-3-yl]amino]-2-oxo-1-phenylethyl]carbamic acid tert-butyl ester

(4S)-4-Amino-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexylamine diammonium salt in a 25 ml flask Acid salt [0.3 M in DMF] (intermediate IIIa, 1.33 ml, 398 μmol, Eq: 1), (S)-2-((t-butoxycarbonyl)amino)-2-phenylacetic acid (0.100 g) 398 μmol, Eq: 1) and HATU (166 mg, 438 μmol, Eq: 1.1) were mixed in DMF (4 ml). Then Hunig's base (257 mg, 348 μl, 1.99 mmol, Eq: 5) was added, and the reaction mixture was stirred at room temperature for 2 hr. It was diluted with EtOAc, poured into ₄ 1M KHSO, and the aqueous layer was extracted with EtOAc (2 x 20ml). The combined organic layer with NaHCO _3, brine, dried and evaporated Na ₂ SO _4. By flash chromatography (silica gel, 20g, in 20% of heptane to 100% EtOAc) to yield purified 124mg of the title compound as a yellow foam; MS: 512.2 (M + H ) +.

B](3R,4S)-4-[[(2S)-2-Amino-2-phenylethenyl]amino]-2,2-difluoro-3-hydroxy-5-methyl-N -(2,2,2-trifluoroethyl)hexylamine

N-[(1S)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2) , 2-trifluoroethylamino)hexane-3-yl]amino]-2-oxo-1-phenylethyl]carbamic acid tert-butyl ester (0.120 g, 235 μmol, Eq: 1) HCl 4M in dioxane (293 μl, 1.17 mmol, Eq: 5) was added to a solution in MeOH (3 ml); the reaction mixture was stirred at room temperature for 2 hr and stirred at 40 ° C for 2 hr. LC-MS indicated the completion of the reaction. The solvent was carefully evaporated to dryness to leave 119mg was used directly in the next step of pale purple foam; MS: 412.2 (M + H ) +.

Prepared in a very similar way:

Intermediate VIb

(3R,4S)-4-[[(2S)-2-Amino-2-(4-chlorophenyl)ethinyl]amino]-2,2-difluoro-3-hydroxy-5-A ke-N-(2,2,2-trifluoroethyl)hexylamine

Substitution of (2S)-2-(4-chlorophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid for (S)-2-((t-butoxy) carbonyl) amino) -2-phenylacetic acid, as a yellow oil; MS: 412.2 (M + H ) +.

Intermediate VIc

(3R,4S)-4-[[(2S)-2-amino-2-(4-methoxyphenyl)ethinyl]amino]-2,2-difluoro-3-hydroxy-5 -methyl-N-(2,2,2-trifluoroethyl)hexylamine

Substituting (2)-2-(4-methoxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid for (S)-2-((Third butoxycarbonyl) amino) -2-phenylacetic acid, as a yellow oil; MS: 442.2 (M + H ) +.

Intermediate VId

(3R,4S)-4-[[(2S)-2-Amino-2-phenylethenyl]amino]-2,2-difluoro-3-hydroxy-5-methyl-N-( 2-morpholin-4-ylethyl)hexylamine

Using (3R,4S)-4-amino-2,2-difluoro-3-hydroxy-5-methyl-N-(2-morpholin-4-ylethyl)hexylamine (Intermediate IIIc) Substituting (4S)-4-amino-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexylamine (Intermediate IIIa) as Light yellow foam; MS: 443.3 (M+H) ⁺ .

Intermediate VIe

(3R,4S)-4-[[(2S)-2-Amino-3-phenylpropanyl]amino]-2,2-difluoro-3-hydroxy-5-methyl-N-( 2,2,2-trifluoroethyl)hexylamine

Substitution of (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropionic acid for (S)-2-((t-butoxycarbonyl)amine )-2-phenylacetic acid.

Intermediates (+)-VII and (-)-VII

(3R)-3-(3,5-dichlorophenyl)-3-phenylpropionic acid (2,5-di-oxypyrrolidin-1-yl) and (3S)-3-(3, 5-dichlorophenyl)-3-phenylpropionic acid (2,5-di-oxypyrrolidin-1-yl) ester

In a 25 mL flask, 3-(3,5-dichlorophenyl)-3-phenylpropanoic acid (572 mg, 1.94 mmol, Eq: 1; Intermediate Id ) and DCM (10 ml) were combined to give a colorless solution. Pyridine (460 mg, 470 μl, 5.81 mmol, Eq: 3), EDC (520 mg, 2.71 mmol, Eq: 1.4) and 1-hydroxypyrrolidine-2,5-dione (268 mg, 2.33 mmol) were added at 0 °C. Eq: 1.2), remove the ice bath and allow the reaction to proceed overnight at room temperature. The reaction mixture was washed with 0.5M KHSO ₄ solution and extracted with suspended DCM (2 x 20mL). The organic layer was washed with saturated NaHCO _3, then washed with H ₂ O / NaCl solution. The organic layer was such compositions, and concentrated in vacuo and dried over Na ₂ SO ₄ and. The crude material was purified by flash chromatography (silica gel, 50g, in 10% of heptane to 70% EtOAc) purification to produce than 566mg as a racemic title compound as a white solid; MS: 295.1 (M-Su ) -.

Separation of 468 mg of its racemic title compound into two image isomers by chromatography with Reprosil on a palm NR column using heptane/30% iPrOH as the eluent to provide the first dissociation product, respectively. 165 mg of (+)-3-(3,5-dichlorophenyl)-3-phenylpropionic acid (2,5-di-oxypyrrolidin-1-yl) ester (Intermediate (+)-VII And 185 mg of (-)-3-(3,5-dichlorophenyl)-3-phenylpropionic acid (2,5-di-oxypyrrolidin-1-yl) ester as a second dissolving product ( Intermediate (-)-VII). Since both samples were contaminated with some free acid, they were again purified by flash chromatography ( 20 g, 10% to 100% AcOEt in heptane) to yield 125 mg of pure (+)-isomer. And 122 mg of pure (-)-isomer.

Example 1

(4S)-4-[[(2S)-2-[3-(3-chlorophenyl)propanylamino]-3-phenylpropanyl]amino]-2,2-difluoro- 5-methyl-N-(2-morpholin-4-ylethyl)-3-oxo-hexylamine

A](3R,4S)-4-[[(2S)-2-[3-(3-chlorophenyl)propanylamino]-3-phenylpropanyl]amino]-2,2 -difluoro-3-hydroxy-5-methyl-N-(2-morpholin-4-ylethyl)hexylamine

In a 10 mL two-necked flask, (S)-2-(3-(3-chlorophenyl)propanylamino)-3-phenylpropionic acid (intermediate IVa, 128 mg, 385 μmol, Eq: 1) and DMF (3 ml) to give a colorless solution; addition of 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisotetrafluoroborate Urea oxime (148 mg, 461 μmol, Eq: 1.2) and Hunig's base (174 mg, 235 μl, 1.35 mmol, Eq: 3.5) and the reaction mixture was stirred at room temperature for 30 min. Next, then (3R,4S)-4-amino-2,2-difluoro-3-hydroxy-5-methyl-N-(2-morpholinoethyl)hexylamine dihydrochloride (middle) The compound IIIc was calculated as the dihydrochloride salt because the last traces of HCl, 0.147 g, 385 μmol, Eq: 1) could not be removed despite careful drying, and the reaction was stirred at room temperature for 2 hours. LC-MS after 2 hours showed that the amidation was completed. The reaction mixture was poured into a 5ml saturated NH ₄ Cl and extracted with DCM (2 x 15mL). The organic layers were combined, washed with brine, dried over Na ₂ CH ₄ By flash chromatography (silica gel, 20g, in DCM to 5% to 10% MeOH) purification to produce the desired electrode shape 205mg of the title product as a light brown oil; MS: 623.5 (M + H ) +.

B](4S)-4-[[(2S)-2-[3-(3-chlorophenyl)propanylamino]-3-phenylpropanyl]amino]-2,2-di Fluoro-5-methyl-N-(2-morpholin-4-ylethyl)-3-oxo-hexylamine

In a 10 mL two-necked flask, the (3R,4S)-4-((S)-2-(3-(3-chlorophenyl)propanylamino)-3-phenylpropionate prepared above was combined. Amino)-2,2-difluoro-3-hydroxy-5-methyl-N-(2-morpholinethyl)hexylamine (0.100 g, 160 μmol, Eq: 1) and DCM (2 ml) A pale yellow solution was produced. Dess-Martin periodinane (499 mg, 366 μl, 177 μmol, Eq: 1.1) was added at 0 ° C and the reaction mixture was stirred at room temperature for 5 hours. 5ml then poured into saturated NH ₄ Cl and extracted with DCM (2 x 10mL). The organic layers were combined, washed with brine, dried over Na ₂ CH ₄ The crude material was purified by flash chromatography (silica gel, 10g, of 0% in DCM to 10% MeOH) was purified to give the title compound 51mg of a pale yellow oil; MS: 621.4 (M + H ) +.

Example 2

(4S)-4-[[(2S)-2-[[(E)-3-(3,5-dichlorophenyl)prop-2-ylindolyl]amino]-2-phenylethyl hydrazide Amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine

A](E)-3-(3,5-dichlorophenyl)prop-2-enoic acid (2,5-di-oxypyrrolidin-1-yl) ester

In a 100 mL pear-shaped flask, (E)-3-(3,5-dichlorophenyl)acrylic acid (1 g, 4.61 mmol, Eq: 1) and DCM (30 ml) were combined to give a white suspension; at 0 ° C Pyridine (1.09 g, 1.12 ml, 13.8 mmol, Eq: 3), EDC (1.24 g, 6.45 mmol, Eq: 1.4) and 1-hydroxypyrrolidine-2,5-dione (689 mg, 5.99 mmol, Eq: 1.3). The ice bath was removed and the reaction mixture was stirred at room temperature overnight (light yellow). The reaction mixture was quenched with 0.5M KHSO ₄ solution and extracted with DCM (2 x 50ml). The organic layer was washed with saturated NaHCO ₃ and washed with brine, concentrated in vacuo and dried over Na ₂ SO ₄ and. Trituration with tributylmethyl ether afforded 1.24 g of the title product as a white solid.

B](3R,4S)-4-[[(2S)-2-[[(E)-3-(3,5-dichlorophenyl)prop-2-enyl]amino]-2- Phenylethyl]amino]-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexylamine

(E)-3-(3,5-Dichlorophenyl)acrylic acid 2,5-di-oxypyrrolidin-1-yl ester (80.7 mg, 257 μmol, Eq: 1) prepared in DME The solution in (4 ml) was added to (3R,4S)-4-[[(2S)-2-amino-2-phenylethenyl]amino]-2,2-di in THF (2 ml) Fluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexylamine (intermediate VIa, 0.085 g, 139 μmol, 54.2% yield) in water (4 ml) A mixture of sodium carbonate (64.7 mg, 770 μmol, Eq: 3). The mixture (light purple solution) was stirred vigorously at room temperature overnight; after completion: the reaction mixture was poured into a 1N KHSO ₄ solution and extracted with AcOEt (2x). The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo; followed by flash chromatography (silica gel, 20g, in 20% of heptane to 100% EtOAc) purified to generate the final 85mg of the title compound as a pale purple solid; MS: 610.2 (M + H ) +.

C](4S)-4-[[(2S)-2-[[(E)-3-(3,5-dichlorophenyl)prop-2-enyl]amino]-2-phenyl Ethyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine

The (3R,4S)-4-[[(2S)-2-[[(E)-3-(3,5-dichlorophenyl)propane-2) prepared above was combined in a 10 mL round bottom flask. -alkenyl]amino]-2-phenylethenyl]amino]-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl Hexamine (0.080 g, 131 μmol, Eq: 1) and DCM (3 ml) to give a colorless solution. 15% Dess-Martin periodinane (556 mg, 408 μl, 197 μmol, Eq: 1.5) in dichloromethane was added at 0 ° C and the reaction mixture was stirred at room temperature. LC-MS after 2 hours showed the reaction was completed. The reaction mixture was extracted with EtOAc (2 x 20mL) saturated with NaHCO ₃ solution and treated. The organic layer was washed with brine, dried (Na ₂ SO ₄₎ and evaporated. By flash chromatography (silica gel, 10g, in heptane of 30% EtOAc) The crude material was purified to yield 10mg of the title compound as a white solid; MS: 608.1 (M + H ) +.

An example of Table 1 was prepared by analogy to Example 1.

An example of Table 2 was prepared by analogy to Example 2.

The asterisk (*) at the palmitic center of the diphenyl methine groups of Examples 74, 77, 78 and 79 represents the palm center, which may have an R or S configuration. The diphenyl methine groups of Examples 74, 77, 78 and 79 did not exist in the form of a racemic mixture in this center.

Example 83

(4S)-4-[[(2S)-2-[[2-(3,5-Dichlorophenoxy)ethinyl]amino]-2-(4-methoxyphenyl) acetamidine Amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine

A](3R,4S)-4-[[(2S)-2-[[2-(3,5-Dichlorophenoxy)ethyl]amino]-2-(4-methoxybenzene) Ethyl)amino]-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexylamine

2-(3,5-Dichlorophenoxy)acetic acid (40.7 mg, 184 μmol, Eq: 1) and N,N-diisopropylethylamine (119 mg, in DMF (4 ml) (4S)-4-((S)-2-Amino-2-(4-methoxyphenyl)acetamido)-2,2-di was added to a mixture of 161 μl, 920 μmol, Eq: 5) Fluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexylamine hydrochloride (Intermediate VIc, 87.9 mg, 184 μmol, Eq: 1) and HATU (84 mg, 221 μmol, Eq: 1.2) and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was quenched with saturated NaHCO ₃ and the mixture was extracted with EtOAc (2 x 25mL). The organic layer was then washed with 1 N KHSO ₄ and with a H ₂ O/NaCI solution. The organic layer was such compositions, and concentrated in vacuo and dried over Na ₂ SO ₄ and. By flash chromatography (silica gel, 20g, in 15% of heptane to 80% EtOAc) was purified to yield 64mg of the title compound as a white foam; MS: 644.1 (M + H ) +.

B](4S)-4-[[(2S)-2-[[2-(3,5-Dichlorophenoxy)ethenyl]amino]-2-(4-methoxyphenyl) Ethyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine

In a 10 mL round bottom flask, the (4S)-4-((S)-2-(2-(3,5-dichlorophenoxy)acetamido)-2-(4) prepared above was combined. -Methoxyphenyl)acetamido)-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexylamine (62 mg, 96.2 Μmol, Eq: 1) and dichloromethane (4 ml) to give a colorless solution. 15% Dess-Martin periodinane (408 mg, 300 μl, 144 μmol, Eq: 1.5) in dichloromethane was added at 0 ° C and the reaction mixture was stirred at room temperature for 2 hours. After completion: the reaction mixture was treated with saturated NaHCO ₃ and extracted with DCM (2 x 20mL). The organic layer was washed with brine, dried (Na ₂ SO ₄₎ and evaporated. The crude material was purified by flash chromatography (silica gel, 10g, 33 is in the% heptane to 50% EtOAc) to afford 49mg of the title product as a white solid; MS: 642.1 (M + H ) +.

An example of Table 3 was prepared by analogy to Example 83.

Example A

The compounds of the formula (I) can be used in the form known per se as active ingredients for the manufacture of lozenges having the following composition:

Instance B

The compounds of the formula (I) can be used in the form known per se as active ingredients for the manufacture of capsules having the following composition:

Claims (30)

a compound of formula (I) Wherein R ¹ is alkyl, substituted cycloalkyl, haloalkyl, substituted heterocycloalkylalkyl, substituted arylalkyl or substituted heteroarylalkyl, wherein substituted ring An alkyl group, a substituted heterocycloalkylalkyl group, a substituted arylalkyl group, and a substituted heteroarylalkyl group are substituted by R ¹⁰ , R ¹¹ and R ¹² ; R ² , R ³ , R ⁴ , R ⁶ , R ⁷ and R ⁹ are independently selected from H, alkyl and cycloalkyl; R ⁵ is substituted aryl, substituted arylalkyl, substituted heteroaryl or substituted hetero arylalkyl, wherein the substituted aryl group, substituted aryl group of, ^13, R ¹⁴ and R ¹⁵ substituents of substituted aryl and substituted heteroaryl of heteroarylalkyl line through R; R ⁸ lines Substituted adamantylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted bicycloalkylalkyl, substituted aryl, substituted arylalkyl, Substituted arylalkenyl, substituted diarylalkyl, substituted aryloxyalkyl, substituted diaryloxyalkyl, substituted arylaryloxyalkyl, substituted hetero Arylaryloxyalkyl group a heteroaryl group, a substituted heteroarylalkyl group, a substituted heteroarylalkenyl group, a substituted arylheteroarylalkyl group, a substituted arylheteroaryloxyalkyl group, or a substituted Aryloxyheteroarylalkyl, wherein substituted adamantylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted bicycloalkylalkyl, substituted aryl Substituted arylalkyl, substituted arylalkenyl, substituted diarylalkyl, substituted aryloxyalkyl, substituted diaryloxyalkyl, substituted aryl An aryloxyalkyl group, a substituted heteroarylaryloxyalkyl group, a substituted heteroaryl group, a substituted heteroarylalkyl group, a substituted heteroarylalkenyl group, a substituted aryl heteroaryl group An alkyl group, a substituted arylheteroaryloxyalkyl group and a substituted aryloxyheteroarylalkyl group are substituted by R ¹⁶ , R ¹⁷ and R ¹⁸ ; R ¹⁰ , R ¹¹ , R ¹² , R ¹³ R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are independently selected from the group consisting of H, halogen, alkyl, haloalkyl, cycloalkyl, cyano, hydroxy, alkoxy, haloalkoxy and benzene Base; or pharmaceutically acceptable . The compound of claim 1, wherein R ¹ is alkyl, substituted cycloalkyl, haloalkyl, substituted heterocycloalkylalkyl, substituted arylalkyl or substituted heteroaryl group, wherein the substituted cycloalkyl, the substituted heterocycloalkyl group, substituted alkyl group and the substituted aryl group of the heteroarylalkyl line by R ^10, R ¹¹ and R ¹² substituents; R ² , R ³ , R ⁴ , R ⁶ , R ⁷ and R ⁹ are independently selected from H, alkyl and cycloalkyl; R ⁵ is substituted aryl, substituted arylalkyl, substituted hetero An aryl or substituted heteroarylalkyl group, wherein the substituted aryl, substituted arylalkyl, substituted heteroaryl, and substituted heteroarylalkyl are via R ¹³ , R ¹⁴ and R ¹⁵ substituted; R ⁸ is substituted adamantylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted dicycloalkylalkyl, substituted aryl, substituted Arylalkyl, substituted arylalkenyl, substituted diarylalkyl, substituted aryloxyalkyl, substituted diaryloxyalkyl, substituted arylaryloxy Alkyl, substituted a substituted heteroarylalkyl group, a substituted heteroarylalkenyl group, a substituted arylheteroarylalkyl group or a substituted aryloxyheteroarylalkyl group, wherein the substituted adamantyl group Alkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted bicycloalkylalkyl, substituted aryl, substituted arylalkyl, substituted arylalkenyl Substituted diarylalkyl, substituted aryloxyalkyl, substituted diaryloxyalkyl, substituted arylaryloxyalkyl, substituted heteroaryl, substituted a heteroarylalkyl group, a substituted heteroarylalkenyl group, a substituted arylheteroarylalkyl group, and a substituted aryloxyheteroarylalkyl group are substituted by R ¹⁶ , R ¹⁷ and R ¹⁸ ; R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are independently selected from H, halogen, alkyl, haloalkyl, cycloalkyl, cyano, hydroxy , alkoxy, haloalkoxy and phenyl; or a pharmaceutically acceptable salt. The compound of claim 1 or 2, wherein R ¹ is alkyl, haloalkyl, substituted heterocycloalkylalkyl or substituted phenylalkyl, wherein substituted heterocycloalkylalkyl and The substituted phenylalkyl group is substituted by R ¹⁰ , R ¹¹ and R ¹² . The compound of claim 1 or 2, wherein R ¹ is haloalkyl. The compound of claim 1 or 2, wherein R ¹⁰ , R ¹¹ and R ¹² are H. A compound of claim 1 or 2 wherein R ⁹ is H. A compound of claim 1 or 2 wherein R ² is alkyl. The compound of claim 1 or 2, wherein R ³ is H. A compound of claim 1 or 2 wherein R ⁴ is H. The compound of claim 1 or 2, wherein R ⁵ is substituted phenyl or substituted phenylalkyl, wherein substituted phenyl and substituted phenylalkyl are via R ¹³ , R ¹⁴ and R ¹⁵ replaced. The compound of claim 1 or 2, wherein R ¹³ , R ¹⁴ and R ¹⁵ are independently selected from the group consisting of H, halogen and alkoxy. The compound of claim 1 or 2, wherein R ¹³ , R ¹⁴ and R ¹⁵ are independently selected from H and halogen. A compound of claim 1 or 2 wherein R ⁶ is H. The compound of claim 1 or 2, wherein R ⁷ is H. A compound according to claim 1 or 2, wherein R ⁸ is a substituted phenylalkyl group, a substituted phenyl alkenyl group, a substituted diphenylalkyl group, a substituted phenoxyalkyl group, substituted Pyridylphenoxyalkyl, substituted phenylpyridyloxyalkyl or substituted phenylphenoxyalkyl, wherein substituted phenylalkyl, substituted phenylalkenyl, substituted The diphenylalkyl group, the substituted phenoxyalkyl group and the substituted phenylphenoxyalkyl group are substituted by R ¹⁶ , R ¹⁷ and R ¹⁸ . The compound of claim 1 or 2, wherein R ⁸ is substituted phenylalkyl, substituted phenylalkenyl, substituted diphenylalkyl, substituted phenoxyalkyl or substituted Phenylphenoxyalkyl, wherein substituted phenylalkyl, substituted phenylalkenyl, substituted diphenylalkyl, substituted phenoxyalkyl, and substituted phenylphenoxy The alkyl group is substituted by R ¹⁶ , R ¹⁷ and R ¹⁸ . The compound of claim 1 or 2, wherein R ⁸ is substituted phenoxyalkyl or substituted phenylphenoxyalkyl, wherein substituted phenoxyalkyl and substituted phenylphenoxy The alkyl group is substituted by R ¹⁶ , R ¹⁷ and R ¹⁸ . The compound of claim 1 or 2, wherein R ¹⁶ , R ¹⁷ and R ¹⁸ are independently selected from H and halogen. The compound of claim 1 or 2, wherein the compound is a compound of formula (Ia) The compound of claim 1 or 2, wherein R ¹ is haloalkyl; R ² is alkyl; R ³ , R ⁴ , R ⁶ , R ⁷ and R ⁹ are H; R ⁵ is substituted phenyl or a substituted phenylalkyl group wherein the substituted phenyl group and the substituted phenylalkyl group are substituted by R ¹³ , R ¹⁴ and R ¹⁵ ; R ⁸ is substituted phenoxyalkyl or substituted phenyl a phenoxyalkyl group, wherein the substituted phenoxyalkyl group and the substituted phenylphenoxyalkyl group are substituted by R ¹⁶ , R ¹⁷ and R ¹⁸ ; R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are independently selected from H and halogen; or a pharmaceutically acceptable salt. A compound according to claim 1 or 2 which is selected from the group consisting of: (4S)-4-[[(2S)-2-[3-(3-chlorophenyl)propanylamino]-3-phenylpropanthene Amino]-2,2-difluoro-5-methyl-N-(2-morpholin-4-ylethyl)-3-oxohexylamine; (S)-4-(( S)-2-((E)-3-(3,5-Dichlorophenyl)acrylamido)-2-phenylacetamido)-2,2-difluoro-5-methyl- 3-Sideoxy-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-(3-(3-chlorophenyl)propanamide (3-) phenyl hydrazinyl)-2,2-difluoro-5-methyl-3-oxo-N-phenethylhexylamine; (S)-4-((S) -2-(3-(3-Chlorophenyl)propanylamino)-3-phenylpropanylamino)-2,2-difluoro-5-methyl-3-oxo-N-( 3,3,3-trifluoropropyl)hexylamine; (S)-4-((S)-2-(3-(3,4-dichlorophenyl)propanylamino)-3-benzene (i) propylamino)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-( (S)-2-(2-(3-Chlorophenoxy)ethylamino)-3-phenylpropanylamino)-2,2-difluoro-5-methyl-3-oxooxy -N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-(2-(3,4-dichlorophenoxy)ethylammonium )-3-phenylpropanylamino)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S )-4-((S) -2-(3-(3,5-dichlorophenyl)propanylamino)-3-phenylpropanylamino)-2,2- Difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-(2-(3) ,5-dichlorophenoxy)ethylamino)-3-phenylpropanylamino)-2,2-difluoro-5-methyl-3-oxo-N-(2,2, 2-(trifluoroethyl)hexylamine; (S)-4-((S)-2-(3-(3-chlorophenyl)propanylamino)-3-phenylpropanylamino)- 2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-( 2-(3,4-Dichlorophenoxy)ethylamino)-3-phenylpropanylamino)-2,2-difluoro-5-methyl-N-(2-morpholinylethyl) -3-oxetyl hexylamine; (S)-4-((S)-2-(2-(3-chlorophenoxy)ethylamino)-3-phenylpropanylamino) -2,2-difluoro-5-methyl-N-(2-morpholinethyl)-3-oxohexylamine; (S)-4-((S)-2-(2-( 3,5-Dichlorophenoxy)ethylamino)-3-phenylpropanylamino)-2,2-difluoro-5-methyl-N-(2-morpholinylethyl)-3 - pendant oxyhexylamine; (S)-4-((S)-2-(3-(3,5-dichlorophenyl)propanylamino)-3-phenylpropanylamino)- 2,2-difluoro-5-methyl-N-(2-morpholinethyl)-3-oxohexylamine; (S)-4-((S)-2-(3-(3) ,4-dichlorophenyl)propanylamino)-3-phenylpropanylamino)-2,2-difluoro-5-methyl-N-(2-morpholinethyl)-3- side Oxyhexylamine; (S)- 4-((S)-2-(3-(3,4-Dichlorophenyl)propanylamino)-3-phenylpropanamido)-2,2-difluoro-5-methyl- 3-sided oxy-N-phenethyl hexylamine; (S)-4-((S)-2-(2-(3-chlorophenoxy)ethylamino)-3-phenylpropane Amidino)-2,2-difluoro-5-methyl-3-oxo-N-phenethylhexylamine; (S)-4-((S)-2-(3-(3) ,4-dichlorophenyl)propanylamino)-3-phenylpropanylamino)-2,2-difluoro-5-methyl-3-o-oxy-N-(3,3,3 -trifluoropropyl)hexylamine; (S)-4-((S)-2-(2-(3,5-dichlorophenoxy)acetamido)-3-phenylpropanamide -2,2-difluoro-5-methyl-3-oxo-N-(3,3,3-trifluoropropyl)hexylamine; (S)-4-((S)- 2-(2-(3-Chlorophenoxy)ethylamino)-3-phenylpropanylamino)-2,2-difluoro-5-methyl-3-oxo-N-( 3,3,3-trifluoropropyl)hexylamine; (S)-4-((S)-2-(3-(3,5-dichlorophenyl)propanylamino)-3-benzene Propionylamino)-2,2- Difluoro-5-methyl-3-oxo-N-(3,3,3-trifluoropropyl)hexylamine; (S)-4-((S)-2-(2-(3) ,4-dichlorophenoxy)ethylamino)-3-phenylpropanylamino)-2,2-difluoro-5-methyl-3-oxo-N-(3,3, 3-trifluoropropyl)hexylamine; (S)-4-((S)-3-(4-chlorophenyl)-2-(3-(3,4-dichlorophenyl)propanamide () phenylamino)-2,2-difluoro-5-methyl-3-oxo-N-phenethylhexylamine; (S)-4-((S)-2-(3 -(3,4-dichlorophenyl)propanylamino)-3-(3,4-dimethoxyphenyl)propanylamino)-2,2-difluoro-5-methyl-3 -Sideoxy-N-phenethylhexylamine; (S)-4-((S)-2-(3-(3,4-dichlorophenyl)propanylamino)-3-(3 ,4-dimethoxyphenyl)propanylamino)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanide Amine; (S)-4-((S)-3-(3,4-dichlorophenyl)-2-(3-(3,4-dichlorophenyl)propanylamino)propylamine -2,2-difluoro-5-methyl-3-oxo-N-phenethylhexylamine; (S)-4-((S)-3-(4-chlorophenyl)- 2-(2-(3,5-Dichlorophenoxy)ethylammonium)propanylamino)-2,2-difluoro-5-methyl-3-oxo-N-(2, 2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-(2-(3,5-dichlorophenoxy)ethinyl)-3-(3) ,4-dichlorophenyl)propanylamino)-2, 2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-(2- (3,5-Dichlorophenoxy)ethylamino)-3-phenylpropanylamino)-N-ethyl-2,2-difluoro-5-methyl-3-oxoyl Indoleamine; (S)-4-((S)-2-(2-(3,5-dichlorophenoxy)ethylamino)-3-phenylpropanylamino)-2,2- Difluoro-N-isobutyl-5-methyl-3-oxohexylamine; (S)-4-((S)-2-(2-(3,5-dichlorophenoxy)) Acetylamino)-3-(3,4-dichlorophenyl)propanylamino)-N-ethyl-2,2-difluoro-5-methyl-3-oxohexylamine; (S)-4-((S)-2-(2-(3,5-Dichlorophenoxy)acetamido)-3-(3,4-dichlorophenyl)propanylamino) -2,2-difluoro-N-isobutyl-5-methyl-3-oxohexylamine; (S)-4-((S)-2-(2-(3,5-di) Chlorophenoxy)ethylamino)-3-(3,4-difluorophenyl)propanylamino)-2,2-difluoro-N-isobutyl-5-methyl-3- side Oxyhexylamine; (S)-4-((S)-3-(4-chlorophenyl)-2-(2-(3,5-dichlorophenoxy)ethylammonium)propanylamino)-2, 2-difluoro-5-methyl-3-oxo-N-(3,3,3-trifluoropropyl)hexylamine; (S)-4-((S)-2-(2- (3,5-Dichlorophenoxy)ethylamino)-3-(3,4-dichlorophenyl)propanylamino)-2,2-difluoro-5-methyl-3-sideoxy -N-(3,3,3-trifluoropropyl)hexylamine; (S)-4-((S)-2-(2-(3,5-dichlorophenoxy)acetamide 3-(3,4-difluorophenyl)propanylamino)-2,2-difluoro-5-methyl-3-oxo-N-(3,3,3-trifluoro Propyl)hexylamine; (S)-4-((S)-2-(2-(3,5-dichlorophenoxy)acetamido)-3-(3,4-dimethoxy Phenyl)propanylamino)-2,2-difluoro-5-methyl-3-oxo-N-(3,3,3-trifluoropropyl)hexylamine; (S)- 4-((S)-2-(2-(3,5-Dichlorophenoxy)ethylamino)-3-phenylpropanylamino)-2,2-difluoro-5-methyl -3-Sideoxy-N-propylhexylamine; (S)-4-((S)-2-(2-(3,5-dichlorophenoxy)ethinyl)-3- Phenylpropionylamino)-2,2-difluoro-5-methyl-N-neopentyl-3-oxohexylamine; (4S)-4-((2S)-2-(3 -(3,4-dichlorophenyl)-3-phenylpropanylamino)-3-phenylpropanamido)-2,2-difluoro-5-methyl-3-oxo- N-(2,2,2-trifluoroethyl)hexanide (S)-4-((S)-3-(4-chlorophenyl)-2-(2-(3,5-dichlorophenoxy)acetamido)propanylamino)-2 ,2-difluoro-5-methyl-3-oxo-N-propylhexylamine; (S)-4-((S)-2-(2-(3,5-dichlorophenoxy) Ethylamino)-3-(3,4-difluorophenyl)propanylamino)-2,2-difluoro-5-methyl-N-neopentyl-3-yloxy Indoleamine; (S)-4-((S)-2-(2-(3,5-dichlorophenoxy)acetamido)-3-(3,4-difluorophenyl)propanthene Amino)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S) -2-(2-(3,5-Dichlorophenoxy)acetamido)-3-(3,4-dimethoxyphenyl)propanylamino)-2,2-difluoro- 5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-((2S)-2-(3-(3,4- Dichlorophenyl)-3-(4-methoxyphenyl)propanylamino)-3-phenylpropanylamino)-2,2-difluoro-5-methyl-3-oxooxy -N-(2,2,2-trifluoroethyl) Hexylamine; (S)-4-((S)-2-((E)-3-(3,4-dichlorophenyl)propenylamino)-3-phenylpropanylamino)- 2,2-difluoro-5-methyl-3-oxo-N-propylhexylamine; (S)-4-((S)-2-((E)-3-(3,4 -dichlorophenyl)acrylamidoamino)-3-phenylpropanylamino)-2,2-difluoro-5-methyl-N-neopentyl-3-oxoxime; S)-4-((S)-2-((E)-3-(3,4-dichlorophenyl)propenylamino)-3-phenylpropanamido)-2,2-di Fluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-((E)-3 -(3,5-dichlorophenyl)propenylamino)-3-phenylpropanylamino)-2,2-difluoro-5-methyl-3-oxo-N-(2, 2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-(4-chlorophenyl)-2-(2-(3,5-dichlorophenoxy) Ethylamino)acetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S) -4-((S)-2-(3,3-diphenylpropanylamino)-3-phenylpropanamido)-2,2-difluoro-5-methyl-3-sideoxy -N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-((2S)-2-(3-(3,5-dichlorophenyl)-3-( 4-methoxyphenyl)propanylamino)-3-phenylpropanylamino)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2 -trifluoroethyl)hexylamine; (4S)-4 -((2S)-3-(4-chlorophenyl)-2-(3-(3,4-dichlorophenyl)-3-phenylpropanylamino)propanylamino)-2,2 -difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-((2S)-2-(3-( 3,4-Dichlorophenyl)-3-phenylpropanylamino)-3-(4-methoxyphenyl)propanylamino)-2,2-difluoro-5-methyl-3 -Sideoxy-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[[(2S)-2-[[2-(3,5-dichlorophenoxy) Ethyl]amino]-2-phenylethenyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-tri Fluoroethyl)hexylamine; (S)-4-((S)-2-(2-(3,5-dichlorophenoxy)acetamido)-2-(4-fluorophenyl) Acetylene Amino)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-((2S) -2-(3-(3,4-Dichlorophenyl)-3-phenylpropanamido)-2-phenylethylamino)-2,2-difluoro-5-methyl-3 -Sideoxy-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-((2S)-2-(4-chlorophenyl)-2-(3-( 3,4-Dichlorophenyl)-3-phenylpropanylamino)acetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2, 2-(trifluoroethyl)hexylamine; (S)-4-((S)-2-(3-(3,4-dichlorophenyl)propanyl)-2-phenylacetamide -2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-((2S)- 2-(3-(4-Bromophenyl)-3-phenylpropanylamino)-3-phenylpropanamido)-2,2-difluoro-5-methyl-3-oxooxy -N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-((2S)-2-(3-(4-bromophenyl)-3-phenylpropanamide 3-(4-chlorophenyl)propanylamino)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl) Hexylamine; (S)-4-((S)-2-((E)-3-(3,4-dichlorophenyl)acrylamido)-2-phenylethylamino)- 2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-( (E)-3-(3-chlorophenyl)propenylamino)-2-benzene Ethylamino)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-( (S)-2-((E)-3-(4-chlorophenyl)acrylamido)-2-phenylacetamido)-2,2-difluoro-5-methyl-3- oxy-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-((2S)-2-(3-(3,5-dichlorophenyl)-3 -Phenylpropionylamino)-2-phenylacetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl Hexylamine; (S)-4-((S)-2-(4-chlorophenyl)-2-((E)-3-(3,4-dichlorophenyl)propenylamino) Ethylamino)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-(( S)-2-(4-chlorophenyl)-2-((E)-3-(3,5-dichlorophenyl)propenylamino)acetamido)-2,2-difluoro- 5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-(4-chlorophenyl)- 2-((E)-3-(3-chlorophenyl)propenylamino)acetamido)-2,2-difluoro-5-methyl-3-o-oxy-N-(2, 2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-(4-chlorophenyl)-2-((E)-3-(4-chlorophenyl)propenylamino)acetamido)-2, 2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-((2S)-2-(3- (3,4-Dichlorophenyl)-3-phenoxypropyl hydrazino)-2-phenylacetamido)-2,2-difluoro-5-methyl-3- oxo- N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-((2S)-2-(3-(3,4-dichlorophenyl)-3-phenoxy Propioninyl-3-phenylpropanylamino)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanide Amine; (4S)-4-((2S)-2-(3-(4-chlorophenoxy)-3-(3,4-dichlorophenyl)propanylamino)-2-phenylethyl Amidino)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-((2S) )-2-(3-(4-chlorophenoxy)-3-(3,4-dichlorophenyl)propanylamino)-3-phenylpropanamido)-2,2-difluoro -5-methyl-3-oxirane-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-((S)-3- (3,5-Dichlorophenyl)-3-phenylpropanylamino)-2-phenylacetamido)-2,2-difluoro-5-methyl-3-oxo-N -(2,2,2-trifluoroethyl)hexylamine; (4S)-4-((2S)-2-(3-(3,5-difluorophenyl)-3-(4-A Oxyphenyl) acrylamido)-2-phenylacetamido -2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-((2S)-2 -(3-(3,5-difluorophenyl)-3-(4-methoxyphenyl)propanylamino)-3-phenylpropanamido)-2,2-difluoro-5 -methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-(4-chlorophenyl)-2 -((S)-3-(3,5-dichlorophenyl)-3-phenylpropanylamino)acetamido)-2,2-difluoro-5-methyl-3-sideoxy -N-(2,2,2-trifluoroethyl)hexylamine; (S)-4-((S)-2-((R)-3-(3,5-dichlorophenyl) 3-phenylpropanylamino)-2-phenylethylamino)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoro Ethyl)hexylamine; (S)-4-((S)-2-(4-chlorophenyl)-2-((R)-3-(3,5-dichlorophenyl)-3- Phenylpropionamide Ethylamino)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; and pharmaceutically acceptable Salt. A compound according to claim 1 or 2 which is selected from the group consisting of: (4S)-4-[[(2S)-2-[[(3S)-3-(3-chlorophenoxy)-3-phenylpropanthene] Amino]-2-(4-chlorophenyl)ethinyl]amino]-2,2-difluoro-5-methyl-3-o-oxy-N-(2,2,2- Trifluoroethyl)hexylamine; (4S)-4-[[(2S)-2-[[(3S)-3-(3-chlorophenoxy)-3-phenylpropanyl]amino) ]-2-phenylethenyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[[(2S)-2-[3-(3,4-Dichlorophenyl)propanylamino]-3-(4-methoxyphenyl)propanyl]amine -2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[[(2S) -2-[[2-(3,5-dichlorophenoxy)ethenyl]amino]-2-(4-methoxyphenyl)ethinyl]amino]-2,2-di Fluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[[(2S)-2-[[3-( 3-chlorophenyl)-3-phenylpropanyl]amino]-2-phenylethenyl]amino]-2,2-difluoro-5-methyl-3-oxo-N -(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[[(2S)-2-(4-chlorophenyl)-2-[[3-(3-chlorobenzene) 3-phenylpropenyl]amino]ethinyl]amino]-2,2-difluoro-5-methyl-3-o-oxy-N-(2,2,2-tri Fluoroethyl) (4S)-4-[[(2S)-2-[[(E)-3-(4-chlorophenyl)prop-2-enyl]amino]-2-(4-methoxy) Phenyl)ethinyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S) -4-[[(2S)-2-[[3-(3,4-dichlorophenyl)-3-phenylpropanyl]amino]-2-(4-methoxyphenyl) Indenyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoro Ethyl)hexylamine; (4S)-4-[[(2S)-2-[[3-(3-chlorophenoxy)-3-(3,4-dichlorophenyl)propanyl] Amino]-2-phenylethenyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexan Amine; (4S)-4-[[(2S)-2-[[3-(3-chlorophenoxy)-3-(3,4-dichlorophenyl)propanyl]amino]-2 -(4-chlorophenyl)ethinyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanide Amine; (4S)-4-[[(2S)-2-[[(3R)-3-(3-chlorophenoxy)-3-phenylpropanyl]amino]-2-phenyl Mercapto]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[ [(2S)-2-[[(3R)-3-(3-chlorophenoxy)-3-phenylpropanyl]amino]-2-(4-chlorophenyl)ethinyl]amine -2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[[(2S) -2-[[(3S)-3-(4-chlorophenoxy)-3-(3,4-dichlorophenyl)propanyl]amino]-2-(4-chlorophenyl) Mercapto]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[ [(2S)-2-[[3-(4-Chlorophenoxy)-3-(3,4-dichlorophenyl)propanyl]amino]-2-phenylethenyl]amino ]-2,2-difluoro-5-methyl-N-(2-morpholine-4 -ylethyl)-3-oxohexylamine; (4S)-4-[[(2S)-2-[[(E)-3-(3,4-dichlorophenyl)propane-2 -alkenyl]amino]-2-phenylethenyl]amino]-2,2-difluoro-5-methyl-N-(2-morpholin-4-ylethyl)-3- (4S)-4-[[(2S)-2-[[2-(3,5-dichlorophenyl) thiomethyl)amino]-3-phenyl Propionyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4- [[(2S)-2-[[3-(3-chlorophenoxy)-3-(5-chloropyridin-3-yl)propanyl]amine 2-phenylethenyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine (4S)-4-[[(2S)-2-[[3-(3-chlorophenyl)-3-pyridin-3-yl-oxo-propenyl]amino]-2-phenylethyl Mercapto]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[ [(2S)-2-[[3-(3-Chlorophenyl)-3-(5-chloropyridin-3-yl)oxypropanyl]amino]-2-(4-methoxybenzene Ethyl)amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; and its medicinal Acceptable salt. A compound according to claim 1 or 2 which is selected from the group consisting of: (4S)-4-[[(2S)-2-[[2-(3,5-dichlorophenoxy)ethenyl]amino]- 3-phenylpropionyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S )-4-[[(2S)-3-(4-chlorophenyl)-2-[[2-(3,5-dichlorophenoxy)ethenyl]amino]propanyl]amine -2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[[(2S)- 2-(4-Chlorophenyl)-2-[[2-(3,5-dichlorophenoxy)ethinyl]amino]ethinyl]amino]-2,2-difluoro-5 -methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[[(2S)-2-[[2-(3,5) -dichlorophenoxy)ethinyl]amino]-2-phenylethenyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2, 2,2-trifluoroethyl)hexylamine; (4S)-4-[[(2S)-2-[[3-(3,4-dichlorophenyl)-3-phenoxypropyl) Amino]-3-phenylpropanyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl) Indoleamine; (4S)-4-[[(2S)-2-[[3-(4-chlorophenoxy)-3-(3,4-dichlorophenyl)propanyl]amino]- 3-phenylpropenyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; (4S)-4-[[(2S)-2-[[3-(4-chlorophenoxy)-3-(3,4-dichlorophenyl)propanyl]amino]-2-benzene Ethyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexylamine; and medicinally Accept the salt. A process for the preparation of a compound according to any one of claims 1 to 23, which comprises: a) reacting a compound of formula (III) with a compound of formula (IV) Then b) reacting the compound of formula (II) under oxidizing conditions Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are as defined in any one of claims 1 to 20. A compound of claim 1 or 2 for use as a therapeutically active substance. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23 and a therapeutically inert carrier. A compound according to claim 1 or 2 for use in wet or dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, early Treatment or prevention of retinopathy of prematurity and polypoidal choroidal vasculopathy. Use of a compound according to any one of claims 1 to 23 for the preparation or treatment of wet or dry age-related macular degeneration, map-like atrophy, diabetic retinopathy, retinopathy of prematurity and polyps An agent for choroidal vasculopathy. Use of a compound according to any one of claims 1 to 23 for the manufacture of a medicament for the treatment or prevention of a condition selected from the group consisting of kidney condition, liver condition, inflammatory condition, wet or dry age Related macular degeneration, map-like atrophy, diabetic retinopathy, retinopathy of prematurity and polypoid choroidal vasculopathy. The compound of claim 1 or 2, which is produced according to the method of claim 21.